WO2015175505A1

WO2015175505A1 - Tetrabenazine modified release formulation

Info

Publication number: WO2015175505A1
Application number: PCT/US2015/030331
Authority: WO
Inventors: Dave Alan MILLER; Justin Martin KEEN; Chris Brough
Original assignee: Lundbeck Llc
Priority date: 2014-05-15
Filing date: 2015-05-12
Publication date: 2015-11-19

Abstract

The present invention relates to new improved tetrabenazine modified release (MR) formulations prepared by use of an advanced amorphous solid dispersion strategy. Said formulations provide a prolonged absorption phase of tetrabenazine providing reduced C_max and increased absorption in the intestinal environment compared to known MR formulations. At the same time said formulations provide an AUC corresponding to an immediate release (IR) formulation.

Description

TETRABENAZINE MODIFIED RELEASE FORMULATION

Field of the invention

Background

Tetrabenazine [1 , 3, 4,6,7, 1 1 b-hexahydro-9, 10-dimethoxy-3-(2-methylpropyl)- 2H-benzo(a)quinolizin-2-one] with the chemical formula shown below was disclosed in 1958 (e.g. GB 789,789 and US 2,830,993) together with a process for its preparation.

The compound has chiral centres at the 3 and 11 b carbon atoms and hence can, theoretically, exist in a total of four isomeric forms, as shown below.

Commercially available tetrabenazine is a racemic mixture of the RR and SS isomers.

Tetrabenazine has been used as a pharmaceutical drug since the late 1950's. Tetrabenazine is currently used in the symptomatic treatment of hyperkinetic movement disorders such as Huntington's disease, hemiballismus, senile chorea, tic, tardive dyskinesia, myoclo- nus, dystonia and Tourette's syndrome, see for example Ondo et al., Am. J. Psychiatry.

(1999), 156(8): 1279-81 and Jankovic and Beach, Neurology (1997), 48(2): 358-62.

Tetrabenazine has a low and variable bioavailability. It is extensively metabolised by first-pass metabolism with cis- and trans-dihydrotetrabenazine [2-hydroxy-3-(2-methylpropyl)- 1 ,3,4,6,7, 11 b-hexahydro-9, 10-dimethoxy-benzo(a)quinolizine] as the major metabolites. Di- hydrotetrabenazine is formed by reduction of the 2-keto group in tetrabenazine. Trans- dihydrotetrabenazine is believed to be primarily responsible for the activity of the drug (see e.g. Roberts et al. , Eur. J. C!in. Pharmacol. (1986), 29: 703-708; ehvar et al. , Drug Metab. Disp. (1987), 15: 250-255 and Mehvar et al., J. Pharm. Sci. (1987), 76(6) : 461 -465 (1987)).

Xenazine (tetrabenazine) is the only FDA-approved treatment for chorea associated with Huntington's disease (see e.g. Yero and Rey, Pharmacy and Therapeutics (2008), 33(12): 690-694) ; however, the safety and efficacy of the treatment is affected by dose limiting side-effects. Specifically, the dose must be titrated for each individual patient via a prolonged dose escalation process. Escalation to the most effective dose is limited by the onset of side-effects, i.e., dose titration is stopped once side effects are experienced. This process introduces a safety concern in the eliciting of side effects in each patient and limits the efficacy of the therapy in that the optimum dose may not be achieved prior to the onset of side effects. There is evidence to support that the side effects associated with tetrabenazine are related to elevated peak plasma concentrations of the active metabolite.

The current commercial tetrabenazine tablet formulation is a standard immediate release (IR) composition designed for rapid and complete release of tetrabenazine in the gastric environment. Human PK profiles obtained after oral administration of a 25 mg IR formulation have been disclosed in e.g. Roberts et al. , Eur. J. Clin. Pharmacol. (1986), 29: 703-708 and Derangula et al. , Biomed Chromatogr. (2013), 27: 792-801 . The oral PK is characterized by a high peak plasma concentration followed by a steep decline in plasma concentration. Mean Tmax is approximately 1 hour and mean t_½ is approximately 2 hours.

Tetrabenazine is a weakly basic compound with relatively good solubility in acidic environments (8.5 mg/mL at pH < 2) and poor solubility in neutral environments (0.03 mg/mL at pH > 4). The solubility of the compound in the gastric environment leads to near-complete absorption from the IR composition following oral administration because the compound is rapidly and completely dissolved and absorbed. Conversely, for a controlled release formulation, the composition passes through the gastric environment allowing for only minimal dissolution of the compound. Consequently, much of the dose is transitioned to the intestinal tract where the pH of the lumen is not conducive to the dissolution of the compound. For example, the pH in the duodenum is about 5-7 and increases to about 7-8 in the ileum and decreases slightly in the colon to 5-7 (Gruber et al. , Adv. Drug. Del. Reviews (1987), 1 :1 -18; Evans et al. , Gut (1988), 29: 1035-141 ). At these pH levels tetrabenazine is practically insoluble. As a re- suit, incomplete absorption is achieved from the intestinal tract, systemic concentrations remain low, and efficacy is compromised.

WO 2012/08 031 aims to provide a solution to problems associated with low solubility and bioavailability of tetrabenazine by providing a crystalline form of tetrabenazine with a high surface area and a defined particle size distribution.

WO 2010/018408 and WO 2011/019956 disclose modified release formulations of tetrabenazine. The PK profiles provided by the MR formulations of WO 201 0/018408 and WO 2011 /019956 are highly affected by the pH solubility profile of tetrabenazine. The MR formulations of WO 2010/018408 and WO 201 1/019956 appear to be substantially affected by the patient's fed state and appear to exhibit incomplete absorption characteristics when taken fasted relative to with a high-fat meal. Because tetrabenazine is vastly more soluble in the gastric versus the intestinal environment, release of the compound from the controlled release tablet largely depends on the duration for which the dosage form is exposed to gastric juices. Therefore, in the fed state where gastric retention is significantly longer, the compound will be released to a greater extent than in the fasted state. This absorption dependence on the fed state of the patient is not acceptable since it creates substantial variations in plasma concentrations and PK parameters such as C_max. This might negatively impact the therapeutic outcome.

There is a need for a new modified release formulation of tetrabenazine with an im- proved PK profile. Particularly, there is a need a for a new modified release formulation of tetrabenazine which produces a PK profile with a blunted C_max compared with an immediate release formulation while maintaining or improving total exposure, even when the formulation is administered in a patient's fasted state. There is also a need for a modified release formulation of tetrabenazine which provides a low variation in PK parameters such as C_max, and fur- thermore, there is a need for a modified release formulation providing a PK profile that is less affected by food intake.

Summary

The present invention concerns an advanced amorphous solid dispersion strategy which is used for providing a new oral modified release formulation of tetrabenazine.

In one embodiment, the present invention relates to a solid dispersion comprising tetrabenazine in amorphous form.

In one embodiment, the invention relates to a pharmaceutical composition comprising tetrabenazine in amorphous form.

In another embodiment, the invention relates to a pharmaceutical composition comprising tetrabenazine, which provides a dissolution profile wherein not more than 80% of the total amount of tetrabenazine added to the vessel has been released from said composition at 2 hours, when said dissolution profile arises from a dissolution experiment performed with an equivalent of 100 mg of tetrabenazine added to a vessel containing 500 ml_ of 0.1 M HCI wherein 167 ml. 0.2 M sodium phosphate tribasic buffer (pH 12) is added to the vessel at 2 hours, wherein said dissolution experiment is performed in a Vankel VK-7000 USP apparatus I I (paddle) dissolution tester at 37°C at a paddle speed of 50 RPM.

In one embodiment, the invention relates to a pharmaceutical composition comprising tetrabenazine, which provides a dissolution profile wherein 30-70% of the total amount of tetrabenazine added to the vessel is in solution at 4 hours, when said dissolution profile arises from a dissolution experiment performed under the conditions described above.

In one embodiment, the invention relates to a pharmaceutical composition comprising tetrabenazine, which provides a dissolution profile wherein 30-60% of the total amount of tetrabenazine added to the vessel is in solution at 6 hours, when said dissolution profile arises from a dissolution experiment performed under the conditions described above.

In another embodiment, the invention relates to a pharmaceutical composition com- prising tetrabenazine, which provides a PK profile in a beagle dog wherein C_max is less than 250 ng/mL; when said PK profile arises from a PK experiment performed in a beagle dog fasted overnight prior to dosing with food returned at 4 hours, wherein said beagle dog immediately after dosing receives an oral flush of 40 ml_ acidified water (pH 2); wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans-dihydrotetrabenazine; and wherein said pharmaceutical composition comprises tetrabenazine in an amount of 25 mg.

In one embodiment, the invention relates to a pharmaceutical composition comprising tetrabenazine, which provides a PK profile in a beagle dog wherein the C_miK standard deviation is less than 60%; when said PK profile arises from a PK experiment performed in a bea- gle dog fasted overnight prior to dosing with food returned at 4 hours, wherein said beagle dog immediately after dosing receives an oral flush of 40 ml_ acidified water (pH 2); wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans-dihydrotetrabenazine.

In one embodiment, the invention relates to a pharmaceutical composition comprising tetrabenazine, which provides a PK profile in a beagle dog wherein C_ma is less than 65% of the Cm_ax obtained by an IR formulation comprising the same amount of tetrabenazine as said pharmaceutical composition; when said PK profile arises from a PK experiment performed under the conditions described above; wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans-dihydrotetrabenazine.

In one embodiment, the invention relates to a pharmaceutical composition comprising tetrabenazine, wherein said pharmaceutical composition provides a PK profile in a beagle dog wherein C_max/AUC_0-inf is in the range of 0.05-0.25 h^"1 : when said PK profile arises from a PK experiment performed under the conditions described above; wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans- dihydrotetrabenazine; wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans-dihydrotetrabenazine.

In another embodiment, the invention relates to a pharmaceutical composition comprising tetrabenazine, which provides a PK profile in a human wherein C_max is less than 50 ng/mL; when said PK profile arises from a PK experiment performed in a human fasted overnight for at least eight hours prior to dosing; wherein said PK profile is based on plasma con- centrations of the sum of tetrabenazine parent and cis- and trans-dihydrotetrabenazine; and wherein said pharmaceutical composition comprises tetrabenazine in an amount of 25 mg.

In one embodiment, the invention relates to a pharmaceutical composition comprising tetrabenazine, which provides a PK profile in a human wherein the C_max standard deviation is less than 60%; when said PK profile arises from a PK experiment performed in a human fast- ed overnight for at least eight hours prior to dosing; wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans- dihydrotetrabenazine; and wherein said pharmaceutical composition comprises tetrabenazine in an amount of 25 mg.

In one embodiment, the invention relates to a pharmaceutical composition comprising tetrabenazine, which provides a PK profile in a human wherein C_max is less than 70%, such as less than 65, 60, 55, 50, 45, 40 or 35% of the C_max obtained by an IR formulation comprising the same amount of tetrabenazine as said pharmaceutical composition; when said PK profile arises from a PK experiment performed in a human fasted overnight for at least eight hours prior to dosing; wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans-dihydrotetrabenazine; and wherein said pharmaceutical composition comprises tetrabenazine in an amount of 25 mg. In one embodiment, the invention relates to a pharmaceutical composition comprising tetrabenazine, which provides a PK profile in a human wherein C_max/AUCo-inf is in the range of 0.05-0.20 h-1 , such as in the range of 0.08-0.17 or 0.10-0.15 h-1 ; when said PK profile arises from a PK experiment per-formed in a human fasted overnight for at least eight hours prior to dosing; wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans-dihydrotetrabenazine; and wherein said pharmaceutical composition comprises tetrabenazine in an amount of 25 mg.

Finally, in one embodiment, the invention relates to a pharmaceutical composition according to the invention for use in the treatment of a hyperkinetic movement disorder such as Huntington's disease, hemiballismus, senile chorea, tic, tardive dyskinesia, myoclonus, dystonia and Tourette's syndrome.

Brief description of drawings

Fig 1 -3: XRPD diffractograms.

X-axis: 2-theta; Y-axis: intensity.

Fig. : XRPD diffractogram of bulk tetrabenazine API measured as described in Example 1.

Fig. 2: XRPD diffractogram of tetrabenazine after first attempt to prepare amorphous form (Ex. 2)

Fig. 3: XRPD diffractogram of amorphous solid dispersion formulation 5 of example 3. Fig. 4: XRPD diffractogram of amorphous solid dispersion formulation 11 of example 3, obtained after four weeks of storage at 40°C and 75% relative humidity.

Fig. 5-7: In vitro dissolution profiles for tetrabenazine tablet formulations obtained according to Example 6. pH change from 1.2 to 6.8 indicated by dotted vertical line.

X-axis: time (hours); Y-axis: tetrabenazine in solution (mg).

- Fig. 5: Formulations 4, 5, 6, 7, 8, 9 and tetrabenazine IR formulation. pH change at approximately 1.3 hours.

■ : formulation 4;♦: formulation 5;■: formulation 6; x : formulation 7;▲: formulation 8; ·: formulation 9; I : IR formulation.

Fig. 6: Formulations 1 0, 11 , 12, 13, 14 and tetrabenazine IR formulation. pH change at approximately 1.05 hours.

I : formulation 10;♦: formulation 1 1 ; A: formulation 12; x : formulation 13; ·: formulation 14.

- Fig. 7: Final formulations 5, 8, 10, 1 1 and tetrabenazine IR formulation. pH change at 2 hours. ♦ : formulation 5; ·: formulation 8;■: formulation 10;▲: formulation 11 ; x : IR formulation.

Fig. 8-18: PK profiles in beagle dogs obtained according to Example 7. Profiles are based on mean plasma concentrations from 4 subjects.

X-axis: time (hours); Y-axis: plasmaconcentration of the sum of the three tetrabenazine analyses; tetrabenazine, cis-dihydrotetrabenazine, and trans-dihydrotetrabenazine (ng/mL). ▲ : MR formulation; ·: tetrabenazine IR formulation.

- Fig. 8: Formulation 4 and tetrabenazine IR formulation.

Fig. 9: Formulation 5 and tetrabenazine IR formulation.

- Fig. 10: Formulation 6 and tetrabenazine IR formulation.

- Fig. 11 : Formulation 7 and tetrabenazine IR formulation.

Fig. 12: Formulation 8 and tetrabenazine IR formulation.

- Fig. 13: Formulation 9 and tetrabenazine IR formulation.

- Fig. 14: Formulation 10 and tetrabenazine IR formulation.

- Fig. 15: Formulation 1 1 and tetrabenazine IR formulation.

- Fig. 16: Formulation 12 and tetrabenazine IR formulation.

Fig. 17: Formulation 13 and tetrabenazine IR formulation.

Fig. 18: Formulation 14 and tetrabenazine IR formulation.

Fig. 19: PK profiles in humans obtained according to Example 8. Profiles are based on mean plasma concentrations from 12 subjects in fasted state.

X-axis: time (hours) ; Y-axis: plasma concentration of the sum of the three tetrabenazine ana- lytes; tetrabenazine, cis-dihydrotetrabenazine, and trans-dihydrotetrabenazine (ng/mL). O : tetrabenazine IR formulation, formulation 5, <>: formulation 8, Δ: formulation 10,□: formulation 11 .

Fig. 20: PK profiles in humans obtained according to Example 8. Profiles are based on mean plasma concentrations from 12 subjects in fed state.

X-axis: time (hours); Y-axis: plasma concentration of the sum of the three tetrabenazine ana- lytes; tetrabenazine, cis-dihydrotetrabenazine, and trans-dihydrotetrabenazine (ng/mL). □ : formulation 1 1 fasted state, O : formulation 11 in fed state.

Definitions

In relation to the current invention, the term "tetrabenazine" (sometimes abbreviated TBZ) indicates tetrabenazine in its free base form. When a dose is specified for tetrabena- zine, said dose is calculated as the free base.

As used herein, tetrabenazine in a "crystalline form" indicates tetrabenazine in a solid form wherein the tetrabenazine molecules are arranged in an ordered pattern extending in all three spatial dimensions. As used herein, tetrabenazine in "amorphous form" or "amorphous tetrabenazine" indicates tetrabenazine in a solid non-crystalline form. The terms "crystalline form" and "amorphous form" are well-known terms for the person skilled in the art.

As used herein, a tetrabenazine "amorphous solid dispersion" or a "solid dispersion comprising tetrabenazine in amorphous form", or a "solid dispersion formulation" indicates a composition in which tetrabenazine is uniformly dispersed in a non-crystalline or substantially non-crystalline form within an excipient matrix. As disclosed herein, a tetrabenazine amorphous solid dispersion may e.g. be formed by a fusion processing method, such as by Ki- netiSol processing as disclosed in e.g. US 2009/00533 5.

As used herein, "pharmaceutical composition" refers to a pharmaceutical dose form including without limitation an oral dose form, such as a solid oral dose form, typically a pill, tablet or capsule. Said pharmaceutical composition typically comprises a therapeutically effective amount of tetrabenazine and one or more pharmaceutically acceptable excipients. "Pharmaceutical compositions of the present invention" refers to all pharmaceutical compositions covered by the claims and description. Pharmaceutical compositions of the present in- vention are intended for administration to mammals such as humans. In a preferred embodiment, said pharmaceutical composition is a tablet formulation such as a tablet formulation comprising a tetrabenazine amorphous solid dispersion. In one embodiment, a pharmaceutical composition of the present invention is referred to as an MR formulation.

As used herein, a tetrabenazine "immediate release" formulation (or "IR" formulation) indicates an oral formulation comprising tetrabenazine providing a dissolution profile wherein the dissolution of tetrabenazine is not influenced by the pharmaceutical excipients in said formulation. As disclosed herein, when an "IR formulation" is used for comparison with an MR formulation e.g. in a dissolution or PK study, said IR formulation is the marketed Xenazine tablet comprising 25 mg of tetrabenazine. In one embodiment, Tetrabenazine in said IR for- mulation is in a crystalline form.

As used herein, a tetrabenazine "modified release" formulation (or "MR" formulation) indicates an oral formulation comprising tetrabenazine, wherein said oral formulation provides an extended dissolution profile compared to the dissolution profile obtained by an IR formulation. Particular mention is made of an MR formulation comprising 25 mg of tetrabenazine.

As used herein, a "unit dosage form" refers to a formulation unit of a pharmaceutical composition. In a preferred embodiment a unit dosage form refers to an oral unit dosage form such as one tablet or capsule.

As used herein, pharmaceutically acceptable carriers and excipients are intended to indicate any pharmaceutically acceptable carriers and excipients suitable for application in formulations comprising a tetrabenazine amorphous solid dispersion such as, but not limited to; mannitol, colloidal silicon dioxide, croscarmellose sodium, carboxymethylcellulose sodium and sodium stearyl fumarate. Remington: The Science and Practice of Pharmacy, 21 Edition, Lippincott Williams & Wilkins, 2006 discloses a variety of pharmaceutically acceptable carriers and excipients.

As used herein, a "PK profile" is an abbreviation of "pharmacokinetic profile". Pharmacokinetic profiles and pharmacokinetic parameters described herein are obtained from the plasma concentration-time data for the sum of tetrabenazine parent and the metabolites cis- and trans-dihydrotetrabenazine using non-compartmental modelling. Abbreviated PK parameters are: C_max (maximum concentration); T_max (time to C_max); t_½ (half-life); AUC₀.i_ast (area under the curve from time of dosing to time of last plasma sample); AUC_0-inf (area under the curve from time of dosing to infinity).

As used herein, "bioavailability" is the oral bioavailability which is the fraction of an administered oral dose of unchanged drug that reaches the systemic circulation.

As used herein, "therapeutically effective amount" of a compound means an amount sufficient to cure, alleviate or partially arrest the clinical manifestations of a given disease and its complications in a therapeutic intervention comprising the administration of said com- pound. The 'therapeutically effective amount" will vary depending on, inter alia, the disease and its severity, and on the age, weight, physical condition and responsiveness of the patient to be treated. Furthermore, the "therapeutically effective amount" may vary if tetrabenazine is combined with one or more other therapeutic agents. In such a case the amount of a given compound might be lower, such as a sub-effective amount. In one embodiment, a "therapeu- tically effective amount" of tetrabenazine is 25 mg.

As used herein, 'treatment" and "treating" refers to the management and care of a patient for the purpose of combating a condition, such as a disease or a disorder. The term is intended to include the full spectrum of treatments for a given condition from which the patient is suffering, such as administration of an active compound to alleviate the symptoms or com- plications, to delay the progression of the disease, disorder or condition, to alleviate or relieve the symptoms and complications, and/or to cure or eliminate the disease, disorder or condition as well as to prevent the condition, wherein prevention is to be understood as the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of the active compounds to prevent the onset of the symptoms or complications. The patient to be treated according to the present is preferably a mammal such a human.

"Hypromellose", an abbreviation for hydroxypropyl methylcellulose (HPMC), is a semisynthetic, inert, viscoelastic polymer used as an ophthalmic lubricant, as well as an excipient and controlled-delivery component in oral medicaments.

"Copovidone" is a copolymer of 1 -vinyl-2-pyrrolidone and vinyl acetate in the mass proportion of 3:2.The average molecular weight of copovidone is usually expressed as a IK- value. Copovidone 64 has a molecular weight in the range of 45.000-70,000. Hypromellose and copovidone are well-known pharmaceutical excipients for the person skilled in the art.

Detailed description of the invention

The present invention concerns an advanced amorphous solid dispersion strategy which is used for providing a new oral modified release formulation of tetrabenazine that can effectively control tetrabenazine release in the gastric environment while providing enhanced dissolution and prolonged release in the intestinal environment.

Previously developed MR formulations of tetrabenazine (WO 2010/018408 and WO

2011/019956) have the disadvantages of being substantially affected by the patient's fed state and appear to exhibit incomplete absorption characteristics when taken fasted relative to with a high-fat meal. The inventors of the present invention have established a method for formulation of a tetrabenazine pharmaceutical composition which provides a modified release of tetrabenazine and at the same time shows good absorption and low PK variability when taken in fasted state. This is illustrated in beagle dogs by PK parameters in Table 5 and PK profiles in Figures 8-18 and in human by PK parameters in Tables 6 and 7 and PK profiles in Figure 19. In fed state the pharmaceutical composition provides an increase in the rate and extent of absorption of tetrabenazine compared to fasted state (illustrated by Table 8 and Figure 20). However, the PK differences observed in fasted versus fed state are significantly smaller than observed with tetrabenazine modified release formulations known in the art.

Amorphous tetrabenazine per se is an unstable substance which rapidly converts to crystalline form at ambient conditions. This has been demonstrated in Example 2 wherein it was attempted to produce amorphous tetrabenazine. The rapid recrystallization is illustrated by the XRD pattern in Figure 2.

The inventors of the present invention have found a method for obtaining a stable pharmaceutical composition comprising amorphous tetrabenazine (see Examples 3-4 and Figures 3-4). The new method implies the conversion of crystalline tetrabenazine into an amorphous form, by application of the solid dispersion technology, to enhance the solubility of the compound in environments of pH greater than 2. In doing so, solubility and dissolution in the intestinal environment is significantly improved allowing for enhanced absorption of tetrabenazine beyond the gastric environment. In the formation of the amorphous solid dispersion, amorphous tetrabenazine may be complexed with one or more functional polymers. The polymers) form a dissolution rate controlling matrix that controls release of tetrabenazine in the gastric environment while enhancing dissolution and generating elevated and prolonged free drug concentrations in the intestinal environment. This modified release profile blunts the C_max of tetrabenazine and its metabolites trans-dihydrotetrabenazine and cis-dihydrotetrabenazine by avoiding a burst-type release in the stomach (illustrated by dog PK profiles in Figures 8- 8 and human PK profile in Figure 19; obtained in fasted dog and human, respectively). Additionally, due to increased intestinal uptake the pharmaceutical composition in both dog and human provides an overall AUC at the same level as a corresponding IR formulation, and fur- thermore, the composition provides a prolonged T_max in human. This may allow for absorption of efficacious systemic concentrations for an extended duration. Finally, the new pharmaceutical composition provides a mean C_max with low variability in both dog and human.

The pharmaceutical composition given in fed state results in an increase in the rate and extent of absorption of tetrabenazine compared to fasted state (illustrated by Table 8 and Figure 20). C_max is still blunted compared to the C_max obtained by giving an IR formulation in fasted state indicating that the new pharmaceutical composition, also when taken with a high- fat meal, does not give burst-type release in the stomach (Table 6, column 2 vs. Table 8, column 3). The PK differences observed in fasted versus fed state are furthermore significantly smaller than PK differences observed with tetrabenazine formulations known in the art. It is possible that food induced PK differences can be further minimized by giving the formulation 1 -2 hours, such as 1 hour before a meal.

In brief, a tetrabenazine amorphous solid dispersion can be processed by the following representative method using a TC-254B KinetiSol compounder designed by DisperSol Technologies (see e.g. US 8,486,423; DiNunzio et al, J.Pharm. Sci. (2010), 99(3) : 1239-1253; Brough and Williams, int. J. Pharm. (201 3), 453: 157-166). Prior to compounding, the crystalline tetrabenazine and excipients are weighed and dispensed into a suitable container and blended for a period of time, for example about 15 minutes. If one or more lubricants are to be included in the composition, the lubricant is added to the primary powder blend and then blended for an additional few minutes. During processing, temperature, rotational speed, and motor amperage are continuously monitored up to the instantaneous discharge of the amorphous solid dispersion upon achieving the setpoint temperature. In some instances, high- purity nitrogen may be used to purge the chamber of oxygen prior to processing. Non-limiting examples of the composition and the processing parameters for amorphous solid dispersions of the invention are presented in Tables 1 and 2.

The amorphous solid dispersion can be incorporated into a final pharmaceutical composition, preferably an oral dosage form such as a tablet dosage form to yield a new tetrabenazine drug product with improved safety, efficacy and convenience.

The solid amorphous dispersions of the present invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses. The pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 21 Edition, Lippincott Williams & Wilkins, 2006. Pharmaceutically acceptable carriers or excipients of the present invention includes but are not limited to mannitol, colloidal silicon dioxide, croscarmellose sodium, carboxymethyl- cellulose sodium, sodium stearyl fumarate. Non-limiting examples of the composition of tablet formulations suitable for formulation of amorphous solid dispersions of the present invention are presented in Table 4.

Tablets are preferably manufactured by milling of the amorphous solid dispersion in a nitrogen environment. All components, with the exception of the glidant and lubricant, are weighed and dispensed and mixed for a period of time, for example 15 minutes at 25 RPM. The glidant and lubricant are then accurately weighed, added, and blended for a period of time, for example an additional 3 minutes. The amorphous solid dispersion may be subsequently compressed, for example with a suitable tableting machine.

Embodiments according to the invention

In the following, embodiments of the invention are disclosed. The first embodiment is denoted E1. the second embodiment is denoted E2 and so forth.

A solid dispersion comprising tetrabenazine in amorphous form. E2. The solid dispersion according to embodiment 1 , wherein the total amount of tetrabenazine constitutes 5-35% (w/w), such as 10-25% (w/w) of said solid dispersion.

E3. The solid dispersion according to embodiment 2, wherein the total amount of tetrabenazine constitutes 18-22% such as 20% (w/w) of said solid dispersion.

E4. The solid dispersion according to any of embodiments 1 -3, comprising a polymer or a combination of at least two polymers.

E5. The solid dispersion according to any of embodiments 1 -4, comprising a polymer se- lected from Hypromellose E3, Hypromellose E5, Hypromellose E50 and Hypromellose

E15 or a combination thereof.

The solid dispersion according to embodiment 5, wherein said Hypromellose E3, Hypromellose E5, Hypromellose E50, Hypromellose E15 or said combination thereof is further combined with Copovidone 64. E7. The solid dispersion according to any of embodiments 4-6, wherein said polymer or polymer combination constitutes 60-80% (w/w), such as 70-76% (w/w) of said solid dispersion. E8. The solid dispersion according to embodiment 7, wherein said polymer or polymer combination constitutes 72-74% (w/w) of said solid dispersion.

E9. The solid dispersion according to any of embodiments 4-8, further comprising an antioxidant or a combination of at least two antioxidants.

E10. The solid dispersion according to any of embodiment 9, wherein said antioxidant is sodium ascorbate.

E1 1 . The solid dispersion according to embodiment 9, wherein said at least two antioxi- dants are selected from sodium ascorbate, butylated hydroxyanisole and butylated hydroxytoluene.

E12. The solid dispersion according to any of embodiments 4-11 , further comprising a lubricant.

E13. The solid dispersion according to embodiment 14, wherein said lubricant is sodium stearyl fumarate.

E14. The solid dispersion according to any of embodiments 1 -13, wherein said solid disper- sion corresponds to a solid dispersion selected from any of solid dispersion formulations 4-8 or 10-14 in Table 1 .

E15. A pharmaceutical composition comprising tetrabenazine in amorphous form. E16. The pharmaceutical composition according to embodiment 15, wherein the total amount of tetrabenazine constitutes 5-35% (w/w), such as 5-25% (w/w) of said pharmaceutical composition.

E17. The pharmaceutical composition according to embodiment 16, wherein the total amount of tetrabenazine constitutes about 10-20% (w/w) of said pharmaceutical composition. E 8. A pharmaceutical composition comprising a solid dispersion according to any of embodiments 1 -14.

E19. The pharmaceutical composition according to embodiment 18, wherein said solid dis- persion constitutes 60-98% (w/w) of said pharmaceutical composition.

E20. The pharmaceutical composition according to any of embodiments 15-19 further comprising one or more pharmaceutically acceptable excipients. E21 . The pharmaceutical composition according to embodiment 20, wherein said pharmaceutically acceptable excipients are selected from one or more of e.g. mannitol, colloidal silicon dioxide, croscarmellose sodium, carboxymethylcellulose sodium and sodium stearyl fumarate. E22. The pharmaceutical composition according to any of embodiments 15-21 , wherein said pharmaceutical composition corresponds to a composition selected from any of tablet formulations 4-8 or 10-14 of Table 3.

E23. The pharmaceutical composition according to any of embodiments 15-21 , wherein said pharmaceutical composition corresponds to a composition selected from any of tablet formulations 5, 8, 10 and 11 of Table 4.

E24. The pharmaceutical composition according to any of embodiments 15-23, which provides a dissolution profile wherein not more than 90% such as not more than 80% of the total amount of tetrabenazine added to the vessel has been released from said composition at 2 hours, when said dissolution profile arises from a dissolution experiment performed with an equivalent of 100 mg of tetrabenazine added to a vessel containing 500 ml_ of 0.1 M HCI wherein 167 ml_ 0.2 M sodium phosphate tribasic buffer (pH 12) is added to the vessel at 2 hours, wherein said dissolution experiment is per- formed in a Vankel VK-7000 USP apparatus II (paddle) dissolution tester at 37°C at a paddle speed of 50 RPM.

E25. The pharmaceutical composition according to any of embodiments 15-24, which provides a dissolution profile wherein 30-70% of the total amount of tetrabenazine added to the vessel is in solution at 4 hours, when said dissolution profile arises from a dissolution experiment performed with an equivalent of 100 mg of tetrabenazine added to a vessel containing 500 mL of 0.1 M HCI wherein 167 ml. 0.2 sodium phosphate tri- basic buffer (pH 12) is added to the vessel at 2 hours, wherein said dissolution experiment is performed in a Vankel VK-7000 USP apparatus II (paddle) dissolution tester at 37°C at a paddle speed of 50 RPM.

E26. The pharmaceutical composition according to embodiment 25, which provides a dissolution profile wherein 40-60% of the total amount of tetrabenazine added to the vessel is in solution at 4 hours.

E27. The pharmaceutical composition according to any of embodiments 15-26, which provides a dissolution profile wherein 30-60% of the total amount of tetrabenazine added to the vessel is in solution at 6 hours, when said dissolution profile arises from a dissolution experiment performed with an equivalent of 100 mg of tetrabenazine added to a vessel containing 500 mL of 0.1 M HCI wherein 167 ml. 0.2 M sodium phosphate tri- basic buffer (pH 12) is added to the vessel at 2 hours, wherein said dissolution experiment is performed in a Vankel VK-7000 USP apparatus II (paddle) dissolution tester at 37°C at a paddle speed of 50 RPM.

E28. The pharmaceutical composition according to embodiment 27, wherein said pharmaceutical composition provides a dissolution profile wherein 40-50% of the total amount of tetrabenazine added to the vessel is in solution at 6 hours.

E29. The pharmaceutical composition according to any of embodiments 15-28, which provides a PK profile in a beagle dog wherein C_max is less than 250 ng/mL; when said PK profile arises from a PK experiment performed in a beagle dog fasted overnight prior to dosing with food returned at 4 hours, wherein said beagle dog immediately after dosing receives an oral flush of 40 mL acidified water (pH 2) ; v/herein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans-dihydrotetrabenazine; and wherein said pharmaceutical composition comprises tetrabenazine in an amount of 25 mg.

E30. The pharmaceutical composition according to embodiment 29, which provides a PK profile in a beagle dog wherein C_max is less than 225 ng/mL, such as less than 200, 175, 150 or 125 ng/mL.

E31 . The pharmaceutical composition according to any of embodiments 15-30, which provides a PK profile in a beagle dog wherein the C_max standard deviation is less than 60%; when said PK profile arises from a PK experiment performed in a beagle dog fasted overnight prior to dosing with food returned at 4 hours, wherein said beagle dog immediately after dosing receives an oral flush of 40 mL acidified water (pH 2); wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans-dihydrotetrabenazine.

E32. The pharmaceutical composition according to embodiment 31 , which provides a PK profile in a beagle dog wherein the C_max standard deviation is less than 50%, such as less than 45, 40, 35, 30, 25 or 20.

The pharmaceutical composition according to any of embodiments 15-32, which provides a PK profile in a beagle dog wherein C_max is less than 65%, such as less than 60, 55, 50, 45, 40, 35 or 30% of the C_max obtained by an IR formulation comprising the same amount of tetrabenazine as said pharmaceutical composition; when said PK profile arises from a PK experiment performed in a beagle dog fasted overnight prior to dosing with food returned at 4 hours, wherein said beagle dog immediately after dosing receives an oral flush of 40 mL acidified water (pH 2) ; v/herein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans-dihydrotetrabenazine. E34. The pharmaceutical composition according to embodiment 33, which provides a PK profile in a beagle dog wherein C_max is in the range of 25-60%, such as in the range of 30-55 or 35-50% of the C_max obtained by an IR formulation comprising the same amount of tetrabenazine as said pharmaceutical composition.

The pharmaceutical composition according to any of embodiments 15-34, which provides a PK profile in a beagle dog wherein C_max/AUCo__inf is in the range of 0.05-0.25 h^" such as in the range of 0.10-0.20 or 0.12-0.18 h^"1 ; when said PK profile arises from a PK experiment performed in a beagle dog fasted overnight prior to dosing with food returned at 4 hours, wherein said beagle dog immediately after dosing receives an oral flush of 40 mL acidified water (pH 2); wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans- dihydrotetrabenazine.

E36. The pharmaceutical composition according to any of embodiments 15-35, which pro- vides a PK profile in a human wherein C_max is less than 50 ng/mL; when said PK profile arises from a PK experiment performed in a human fasted overnight for at least eight hours prior to dosing; wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans-dihydrotetrabenazine; and wherein said pharmaceutical composition comprises tetrabenazine in an amount of 25 mg. E37. The pharmaceutical composition according to embodiment 36, which provides a PK profile in a human wherein C_mai is less than 45 ng/ml_, such as less than 40, 35, 30 or 25 ng/mL.

E38. The pharmaceutical composition according to any of embodiments 15-37, which pro- vides a PK profile in a human wherein the C_max standard deviation is less than 60%; when said PK profile arises from a PK experiment performed in a human fasted overnight for at least eight hours prior to dosing; wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans- dihydrotetrabenazine; and wherein said pharmaceutical composition comprises tetra- benazine in an amount of 25 mg.

E39. The pharmaceutical composition according to embodiment 38, which provides a PK profile in a human wherein the C_max standard deviation is less than 55%, such as less than 50, 45 or 40%.

E40. The pharmaceutical composition according to any of embodiments 15-39, which provides a PK profile in a human wherein C_max is less than 70% such as less than 65, 60, 55, 50, 45, 40 or 35 % of the C_ma)< obtained by an IR formulation comprising the same amount of tetrabenazine as said pharmaceutical composition; when said PK profile arises from a PK experiment performed in a human fasted overnight for at least eight hours prior to dosing; wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans-dihydrotetrabenazine; and wherein said pharmaceutical composition comprises tetrabenazine in an amount of 25 mg. E41 . The pharmaceutical composition according to embodiment 40, which provides a PK profile in a human wherein C_max is in the range of 35-70%, such as in the range of 40- 70 or 40-65% of the C_max obtained by an IR formulation comprising the same amount of tetrabenazine as said pharmaceutical composition. E42. The pharmaceutical composition according to any of embodiments 15-41 , which provides a PK profile in a human wherein C_max/AUCo-inf is in the range of 0.05-0.20 h^'1, such as in the range of 0.08-0.17 or 0.10-0.15 h^"1 ; when said PK profile arises from a PK experiment performed in a human fasted overnight for at least eight hours prior to dosing; wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans-dihydrotetrabenazine; and wherein said pharmaceutical composition comprises tetrabenazine in an amount of 25 mg.

E43. A pharmaceutical composition comprising tetrabenazine, which provides a dissolution profile wherein not more than 90% such as not more than 80% of the total amount of tetrabenazine added to the vessel has been released from said composition at 2 hours, when said dissolution profile arises from a dissolution experiment performed with an equivalent of 100 mg of tetrabenazine added to a vessel containing 500 mL of

0.1 M HCI wherein 167 mL 0.2 M sodium phosphate tribasic buffer (pH 12) is added to the vessel at 2 hours, wherein said dissolution experiment is performed in a Vankel VK-7000 USP apparatus II (paddle) dissolution tester at 37°C at a paddle speed of 50 RPM.

E44. A pharmaceutical composition comprising tetrabenazine, which provides a dissolution profile wherein 30-70% of the total amount of tetrabenazine added to the vessel is in solution at 4 hours, when said dissolution profile arises from a dissolution experiment performed with an equivalent of 100 mg of tetrabenazine added to a vessel containing 500 mL of 0.1 M HCI wherein 167 mL 0.2 M sodium phosphate tribasic buffer (pH 12) is added to the vessel at 2 hours, wherein said dissolution experiment is performed in a Vankel VK-7000 USP apparatus II (paddle) dissolution tester at 37°C at a paddle speed of 50 RPM E45. The pharmaceutical composition according to embodiment 43, which provides a dissolution profile wherein 30-70% of the total amount of tetrabenazine added to the vessel is in solution at 4 hours.

E46. The pharmaceutical composition according to any of embodiments 44-45, which pro- vides a dissolution profile wherein 40-60% of the total amount of tetrabenazine added to the vessel is in solution at 4 hours.

E47. A pharmaceutical composition comprising tetrabenazine, which provides a dissolution profile wherein 30-60% of the total amount of tetrabenazine added to the vessel is in solution at 6 hours, when said dissolution profile arises from a dissolution experiment performed with an equivalent of 100 mg of tetrabenazine added to a vessel containing 500 mL of 0.1 M HCI wherein 167 mL 0.2 M sodium phosphate tribasic buffer (pH 12) is added to the vessel at 2 hours, wherein said dissolution experiment is performed in a Vankel VK-7000 USP apparatus II (paddle) dissolution tester at 37°C at a paddle speed of 50 RPM E48. The pharmaceutical composition according to any of embodiments 43-46, which provides a dissolution profile wherein 30-60% of the total amount of tetrabenazine added to the vessel is in solution at 6 hours.

E49. The pharmaceutical composition according to any of embodiments 47-48, which pro- vides a dissolution profile wherein 40-50% of the total amount of tetrabenazine added to the vessel is in solution at 6 hours.

E50. A pharmaceutical composition comprising tetrabenazine, which provides a PK profile in a beagle dog wherein C_max is less than 250 ng/mL; when said PK profile arises from a PK experiment performed in a beagle dog fasted overnight prior to dosing with food returned at 4 hours, wherein said beagle dog immediately after dosing receives an oral flush of 40 ml_ acidified water (pH 2); wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans- dihydrotetrabenazine; and when said pharmaceutical composition comprises tetra- benazine in an amount of 25 mg.

E51 . The pharmaceutical composition according to any of embodiments 43-49, which provides a PK profile in a beagle dog wherein C_max is less than 250 ng/mL; when said PK profile arises from a PK experiment performed in a beagle dog fasted overnight prior to dosing with food returned at 4 hours, wherein said beagle dog immediately after dosing receives an oral flush of 40 imL acidified water (pH 2) ; wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans-dihydrotetrabenazine; and when said pharmaceutical composition comprises tetrabenazine in an amount of 25 mg.

E52. The pharmaceutical composition according to any of embodiments 50-51 , which provides a PK profile in a beagle dog wherein C_max is less than 225 ng/mL, such as less than 200, 175, 150 or 125 ng/mL. E53. A pharmaceutical composition comprising tetrabenazine, which provides a PK profile in a beagle dog wherein the C_max standard deviation is less than 60%; when said PK profile arises from a PK experiment performed in a beagle dog fasted overnight prior to dosing with food returned at 4 hours, wherein said beagle dog immediately after dosing receives an oral flush of 40 mL acidified water (pH 2); v/herein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans-dihydrotetrabenazine.

E54. The pharmaceutical composition according to any of embodiments 43-52, which provides a PK profile in a beagle dog wherein the C_max standard deviation is less than 60%; when said PK profile arises from a PK experiment performed in a beagle dog fasted overnight prior to dosing with food returned at 4 hours, wherein said beagle dog immediately after dosing receives an oral flush of 40 mL acidified water (pH 2); wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans-dihydrotetrabenazine.

E55. The pharmaceutical composition according to any of embodiments 53-54, which provides a PK profile in a beagle dog wherein the C_max standard deviation is less than 50%, such as less than 45, 40, 35, 30, 25 or 20%.

E56. A pharmaceutical composition comprising tetrabenazine, which provides a PK profile in a beagle dog wherein C_max is less than 65%, such as less than 60, 55, 50, 45, 40, 35 or 30% of the C_max obtained by an IR formulation comprising the same amount of tetrabenazine as said pharmaceutical composition; when said PK profile arises from a PK experiment performed in a beagle dog fasted overnight prior to dosing with food returned at 4 hours, wherein said beagle dog immediately after dosing receives an oral flush of 40 mL acidified water (pH 2); wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans- dihydrotetrabenazine.

E57. The pharmaceutical composition according to any of embodiments 43-55, which provides a PK profile in a beagle dog wherein C_max is less than 65%, such as less than 60, 55, 50, 45, 40, 35 or 30% of the C_max obtained by an IR formulation comprising the same amount of tetrabenazine as said pharmaceutical composition; when said PK profile arises from a PK experiment performed in a beagle dog fasted overnight prior to dosing with food returned at 4 hours, wherein said beagle dog immediately after dosing receives an oral flush of 40 mL acidified water (pH 2) ; v/herein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans-dihydrotetrabenazine. E58. The pharmaceutical composition according to any of embodiments 56-57, which provides a PK profile in a beagle dog wherein C_max is in the range of 25-60%, such as in the range of 30-55 or 35-50% of the C obtained by an IR formulation comprising the same amount of tetrabenazine as said pharmaceutical composition.

E59. A pharmaceutical composition comprising tetrabenazine, wherein said pharmaceutical composition provides a PK profile in a beagle dog wherein C_max/AUC₀._inf is in the range of 0.05-0.25 h^"1, such as in the range of 0. 0-0.20 or 0.12-0.1 8 h^"1 ; when said PK profile arises from a PK experiment performed in a beagle dog fasted overnight prior to dosing with food returned at 4 hours, wherein said beagle dog immediately after dosing receives an oral flush of 40 ml_ acidified water (pH 2); wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans-dihydrotetrabenazine. E60. The pharmaceutical composition according to any of embodiments 43-58, which provides a PK profile in a beagle dog wherein C_max/AUCo_in_f is in the range of 0.05-0.25 h^"1, such as in the range of 0.10-0.20 or 0.12-0.18 h^"1; when said PK profile arises from a PK experiment performed in a beagle dog fasted overnight prior to dosing with food returned at 4 hours, wherein said beagle dog immediately after dosing receives an oral flush of 40 ml_ acidified water (pH 2); wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans- dihydrotetrabenazine.

E61 . A pharmaceutical composition comprising tetrabenazine, which provides a PK profile in a human wherein C_max is less than 50 ng/mL; when said PK profile arises from a PK experiment performed in a human fasted overnight for at least eight hours prior to dosing; wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans-dihydrotetrabenazine; and wherein said pharmaceutical composition comprises tetrabenazine in an amount of 25 mg.

E62. The pharmaceutical composition according to any of embodiments 43-60, which provides a PK profile in a human wherein C_max is less than 50 ng/mL; when said PK profile arises from a PK experiment performed in a human fasted overnight for at least eight hours prior to dosing; wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans-dihydrotetrabenazine: and wherein said pharmaceutical composition comprises tetrabenazine in an amount of 25 mg. E63. The pharmaceutical composition according to any of embodiments 61 -62, which provides a PK profile in a human wherein C_max is less than 45 ng/nriL, such as less than

E64. A pharmaceutical composition comprising tetrabenazine, which provides a PK profile in a human wherein the C_max standard deviation is less than 60%; when said PK profile arises from a PK experiment performed in a human fasted overnight for at least eight hours prior to dosing; wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans-dihydrotetrabenazine: and wherein said pharmaceutical composition comprises tetrabenazine in an amount of 25 mg.

The pharmaceutical composition according to any of embodiments 43-63, which provides a PK profile in a human wherein the C_max standard deviation is less than 60%; when said PK profile arises from a PK experiment performed in a human fasted overnight for at least eight hours prior to dosing; wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans- dihydrotetrabenazine; and wherein said pharmaceutical composition comprises tetrabenazine in an amount of 25 mg.

The pharmaceutical composition according to any of embodiments 64-65, which provides a PK profile in a human wherein the C_max standard deviation is less than 55%, such as less than 50, 45 or 40%.

A pharmaceutical composition comprising tetrabenazine, which provides a PK profile in a human wherein C_max is less than 70%, such as less than 65, 60, 55, 50_: 45, 40 or 35%) of the Cmax obtained by an IR formulation comprising the same amount of tetrabenazine as said pharmaceutical composition; when said PK profile arises from a PK experiment performed in a human fasted overnight for at least eight hours prior to dosing; wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans-dihydrotetrabenazine; and wherein said pharmaceutical composition comprises tetrabenazine in an amount of 25 mg. E68. The pharmaceutical composition according to any of embodiments 43-66, wherein said pharmaceutical composition provides a PK profile in a human wherein C_max is less than 70%, such as less than 65, 60, 55, 50, 45, 40 or 35% of the C_ma( obtained by an IR formulation comprising the same amount of tetrabenazine as said pharmaceutical composition; when said PK profile arises from a PK experiment performed in a human fasted overnight for at least eight hours prior to dosing; wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans-dihydrotetrabenazine; and wherein said pharmaceutical composition comprises tetrabenazine in an amount of 25 mg.

E69. The pharmaceutical composition according to any of embodiments 67-68, which provides a PK profile in a human wherein C_max is in the range of 35-70%, such as in the range of 40-70 or 40-65% of the C_max obtained by an IR formulation comprising the same amount of tetrabenazine as said pharmaceutical composition.

E70. A pharmaceutical composition comprising tetrabenazine, which provides a PK profile in a human wherein C_max/AUCo-inf is in the range of 0.05-0.20 h^"1, such as in the range of 0.08-0.17 or 0.10-0.15 h^"1 ; when said PK profile arises from a PK experiment performed in a human fasted overnight for at least eight hours prior to dosing; wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans-dihydrotetrabenazine; and wherein said pharmaceutical composition comprises tetrabenazine in an amount of 25 mg.

E71 . The pharmaceutical composition according to any of embodiments 43-69, which provides a PK profile in a human wherein C_max/AUCo.in_f is in the range 0.05-0.20 h^"1, such as in the range of 0.08-0.17 or 0.10-0.1 5 h^"1 ; when said PK profile arises from a PK experiment performed in a human fasted overnight for at least eight hours prior to dos- ing; wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans-dihydrotetrabenazine; and wherein said pharmaceutical composition comprises tetrabenazine in an amount of 25 mg.

E72. The pharmaceutical composition according to any of embodiments 50-60, wherein said PK profile arises from a PK experiment performed as described in Example 7.

E73. The pharmaceutical composition according to any of embodiments 61 -71 , wherein said PK profile arises from a PK experiment performed as described in Example 8. E74. The pharmaceutical composition according to any of embodiments 43-73, wherein said tetrabazine in said pharmaceutical composition is tetrabenazine in amorphous form. E75. The pharmaceutical composition according to any of embodiments 15-74, wherein the total amount of tetrabenazine is in the range of 1 0-100 mg, such as 10, 1 5, 20, 25, 30, 35, 40, 50, 75 or 100 mg

E76. The pharmaceutical composition according to embodiment 75, wherein the total amount of tetrabenazine is 25 mg.

The pharmaceutical composition according to any of embodiments 15-76, wherein said pharmaceutical composition is an oral unit dosage form such as a tablet or a capsule.

E78. The pharmaceutical composition according to embodiment 77, wherein said composition is a tablet.

E79. The pharmaceutical composition according to any of embodiments 15-78, wherein said tetrabenazine is the sole therapeutic agent comprised in said composition.

E80. The pharmaceutical composition according to any of embodiments 15-79, further comprising a second therapeutic agent.

E81 . The pharmaceutical composition according to any of embodiments 15-80 for use in the treatment of a hyperkinetic movement disorder such as Huntington's disease, hemiballismus, senile chorea, tic, tardive dyskinesia, myoclonus, dystonia and Tou- rette's syndrome.

A method for the treatment of a hyperkinetic movement disorder such as Huntington's disease, hemiballismus, senile chorea, tic, tardive dyskinesia, myoclonus, dystonia and Tourette's syndrome, by administration of a pharmaceutical composition according to any of embodiments 15-81 to a patient in need thereof.

All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference in their entirety and to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein (to the maximum extent permitted by law), regardless of any separately provided incorporation of particular documents made elsewhere herein. The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. For example, the phrase "the solid dispersion" is to be understood as referring to various "solid dispersions" of the invention or particular described aspect, unless otherwise indicated.

The description herein of any aspect or aspect of the invention using terms such as "comprising", "having," "including," or "containing" with reference to an element or elements is intended to provide support for a similar aspect or aspect of the invention that "consists of", "consists essentially of", or "substantially corn-prises" that particular element or elements, unless otherwise stated or clearly contradicted by context (e.g., a composition described herein as comprising a particular element should be understood as also describing a composition consisting of that element, unless otherwise stated or clearly contradicted by context).

It should be understood that the various aspects, embodiments, implementations and features of the invention mentioned herein may be claimed separately, or in any combination.

The invention is further illustrated by the following non-limiting examples.

Examples

Example 1: X-ray diffraction (XRD) analysis

X-ray diffraction (XRD) analyses of bulk tetrabenazine API and samples from Examples 2, 3 and 4 were conducted using an Inel Equinox 100 benchtop x-ray diffractometer. Samples were placed in an aluminium crucible and loaded in a rotating sample holder. Samples were analysed for 600 seconds using a Cu K radiation source (λ = 1.5418 A) operating at 42 kV and 0.81 mA. XRD pattern of bulk tetrabenazine API is shown in Figure 1 illustrating tetrabenazine on crystalline form.

Example 2: Attempt to make amorphous tetrabenazine

The production of amorphous tetrabenazine was attempted by a flash evaporation process in a BUCHI rotovap system. Pure tetrabenazine was fully dissolved in acetone before rotary evaporation. Solvent was evaporated under vacuum with slight heat. Evaporated solvent was condensed in the recirculating chilling system and collected.

XRD Result:

XRD pattern of the rotary evaporated pure tetrabenazine sample is shown in figure 2. It is seen from this figure that pure tetrabenazine immediately and completely recrystallized following solvent evaporation. Hence, the experiment to produce amorphous tetrabenazine was unsuccessful owing to the rapid crystallization kinetics of tetrabenazine. This indicates that tetrabenazine is not physically stable in the amorphous form at ambient conditions. Example 3: Preparation of amorphous solid dispersions

Processing was performed using a TC-254B KinetiSol compounder designed by Dis- perSol Technologies (see US 2009/00533 5). Prior to compounding, crystalline tetrabenazine and excipients were accurately weighed and dispensed into a suitable container and blended for 15 minutes with a Maxi-Blend lab blender fitted with the bottle blending attachment. When the formulation included lubricant, the lubricant was added to the primary powder blend and then blended for an additional 2 minutes. A total batch size of 80 g of powder blend charged to the KinetiSol chamber was used for each trial. During processing, temperature, rotational speed, and motor amperage were continuously monitored up to the instantaneous discharge of the amorphous solid dispersion upon achieving the setpoint temperature. In some instances, high-purity nitrogen was used to purge the chamber of oxygen prior to processing.

Quantitative composition and processing parameters for amorphous solid dispersions are listed in Tables 1 and 2, respectively.

Table 1: Quantitative composition of amorphous solid dispersions 4- 14.

Solid dispersion formulation

4 5 6 7 8 9

Component Percent (w/w)

Tetrabenazine 20.0 20.0 20.0 20.0 20.0 20.0

Hypromellose E3 72.9 72.9 72.9 - - -

Hypromellose E5 - - - - 72.9 -

Hypromellose E50 - - - - - -

Hypromellose E15 - - - 72.9 - -

Copovidone 64 - - - - - 72.9

Butylated Hydrox-

0.8 0.8 0.8 0.8 0.8 0.8 yanisole

Butylated Hydroxy-

0.3 0.3 0.3 0.3 0.3 0.3 toluene

Sodium Ascorbate 4.0 4.0 4.0 4.0 4.0 4.0

Sodium Stearyl

2.0 2.0 2.0 2.0 2.0 2.0 Fumarate

Solid dispersion formulation

10 11 12 13 14

Component Percent (w/w)

Tetrabenazine 20.0 20.0 20.0 10.0 20.0

Hypromellose E3 - - - - 55.3

Hypromellose E5 - - 55.3 62.2 -

Hypromellose E50 36.5 - - - -

Hypromellose E15 - 55.3 - - -

Copovidone 64 36.5 17.6 17.6 20.7 17.6

Butylated Hydrox-

0.8 0.8 0.8 0.8 0.8 yanisole

Butylated Hydroxy-

0.3 0.3 0.3 0.3 0.3 toluene

Sodium Ascorbate 4.0 4.0 4.0 4.0 4.0

Sodium Stearyl

2.0 2.0 2.0 2.0 2.0

Fumarate Table 2: Processing parameters for amorphous solid dispersions 4-14.

Solid dispersion formulation

4 5 6 7

RPM 1 ,700 1 ,700 1 ,700 2,500

Ejection temperature (°C) 90 90 90 90

Batch size (g) 80 80 80 80

Chamber N2 purge Yes Yes Yes Yes

Quenching method N2 (I) N2 (I) N2 (I) N2 (I)

Vacuum equilibration to ambient 1 hr 1 hr 1 hr 1 hr

Hypro- Hypro- Hypro- Hypro-

Polymer pre-drying mellose - 60 mellose - 60 mellose - 60 mellose - 60

°C > 3 hrs °C > 3 hrs °C > 3 hrs °C > 3 hrs

Solid dispersion formulation

8 9 10 11

RPM 2,000 1 ,800 1 ,700 2,000

Ejection temperature (°C) 90 85 90 90

Batch size (g) 80 80 80 80

Chamber N2 purge Yes Yes Yes Yes

Quenching method N2 (I) N2 (I) N2 (I) N2 (I)

Vacuum equilibration to ambient 1 hr 1 hr 1 hr 1 hr

Hypro- Hypro- mellose - 60 mellose - 60

Copovidone

°C > 3 °C > 3 Co¬

Hypro- 64 - vacuum

Copovidone povidone 64

Polymer pre-drying mellose - 60 with des- 64 - vacuum - vacuum °C > 3 hrs sicant overwith des- with des- night

sicant oversicant overnight night

Solid dispersion formulation

12 13 14

RPM 2,300 2,300 2,300

Ejection temperature (°C) 100 90 90

Batch size (g) 80 80 80

Chamber N2 purge Yes Yes Yes

Quenching method N2 (I) N2 (I) N2 (I)

Vacuum equilibration to ambient 1 hr 1 hr 1 hr

Hypro- Hypro- Hypro- mellose - 60 mellose - 60 mellose - 60

°C > 3 hrs °C > 3 hrs °C > 3 CoCopovidone Copovidone povidone 64

Polymer pre-drying

64 - vacuum 64 - vacuum - vacuum

with des- with des- with des- sicant oversicant oversicant overnight night night

XRD Results:

A typical XRD pattern for an amorphous solid dispersion (solid dispersion formulation 5) is shown in Figure 3 which clearly illustrates that tetrabenazine is in amorphous form. Similar XRD patterns were obtained from formulations 4 and 6-14. Example 4: Physical stability of tetrabenazine amorphous solid dispersion formulation

To evaluate the physical stability of the tetrabenazine amorphous solid dispersion formulations, compositions made according to Example 3 were packaged in aluminium induction sealed high-density polyethylene bottles with desiccant and stored in a controlled environmental chamber maintained at 40 °C and 75% relative humidity for a period of four weeks. At the designated time point, samples were removed from the chamber and analysed by XRD according to the method described in Example 1 .

XRD Results:

Figure 4 is a representative XRD pattern of the amorphous tetrabenazine dispersions after four weeks of storage at 40 °C and 75% relative humidity. Specifically, the composition is that of Formulation 1 1 presented in Example 3. The XRD pattern exhibits the absence of all tetrabenazine related crystalline peaks indicating that the tetrabenazine composition is physically stable at accelerated storage conditions.

Example 5: Preparation of tablets

Milling of the tetrabenazine amorphous solid dispersions was performed using a Fitz- patrick L1 A FitzMill (Fitzpatrick, Inc. , Elmhurst, IN, USA) in hammer forward orientation, oper- ating at an RPM range of 4,000 - 7,000 depending on the composition equipped with a 0.02" screen. To minimize oxidation of tetrabenazine in the Al, milling was conducted in a nitrogen environment for the final stability batches. Particle size distribution measurements were performed using an Advantech Model L3P (Advantech Manufacturing, New Berlin, Wl) sonic sift- er separator with a sieve stack assembly based on ASTM standards.

The prototype tablets were produced on a small-scale; sufficient for producing tablets in quantities for in-vitro dissolution testing, dog PK analysis, and basic stability testing. Tablet- ing blends were prepared by accurately weighting all components, with the exception of the glidant and lubricant, into a glass bottle and mixing for 15 minutes at 25 RPM using a Maxi- Blend lab blender (GlobePharma, New Brunswick, NJ) fitted with the bottle blending attachment. The glidant and lubricant were then accurately weighed, added to the bottle, and blended for an additional 3 minutes.

For tablet production, an MTMC-I I manual tablet machine (GlobePharma, New Brunswick, NJ) fitted with 8 mm round, shallow concave tablet tooling was used to compress the tablets. Aliquots of the powder blend were accurately weighed individually to the target weight of the tablets, fed into the tablet die, and compressed up to a gauge pressure of 1 ,200 psi. Tablet hardness was measured using a VanKel VK200 hardness tester (Varian, Inc.). Where needed tablet hardness was optimized by adjusting the tablet formulation.

Table 3 below indicates the quantitative composition of the tablet formulations used in dog PK studies. Each formulation contains the amorphous solid dispersion of table 2 corresponding to the tablet formulation No. , e.g. tablet formulation 4 contains amorphous solid dispersion 4 of table 2. The final amount of tetrabenazine in all formulations is 25 mg.

Table 3: Quantitative com osition of tablet formulations 4-14 used in do PK studies.

Because of poor compatibility between amorphous tetrabenazine and calcium phos- phate dibasic dihydrate, slightly modified formulations 5, 8, 10 and 1 wherein calcium phosphate dibasic dihydrate was replaced with a combination of mannitol and carboxymethylcellu- lose sodium, were selected for human PK study. The quantitative compositions of final tablet formulations for clinical PK studies are listed in Table 4 below. Table 4: Quantitative composition of final tablet formulations 5, 8, 10 and 11 for use in clinical PK studies.

Tablet cores were coated with a solvent-based film coating. A Eudragit EPO (Evonik Industries) coating system was utilized and applied from a 15% percent by weight solution in acetone. The polymer was allowed to stir in the solvent for 5 to 10 minutes prior to coating, or until the solution became clear. The tablet substrates were arranged in a single layer on a perforated pan under a heat lamp and maintained at a temperature of 45° C for the duration of coating. Atomization of the coating solution was achieved by the use of a Paasche H air- brush with an inlet compressed air pressure of approximately 25 psi. The tablets were coated to an average weight gain of 5%. Following coating the tablets were allowed to dry for 10 minutes under the heat lamp. Subsequently, the tablets were placed in a nitrogen purged environment to dry overnight. The EPO coated tablets were then packaged in either an Oxy- Guard or Mylar bag packaging configuration and placed on stability. Example 6: in vitro dissolution experiments (gastric transfer dissolution testing)

ln-vitro dissolution testing was employed to screen tablet formulations 4-14, in the development and selection of tablet prototypes for the dog PK study, and for clinical candidate selection. Owing to the pH solubility profile of tetrabenazine; i.e. , 8.5 mg/mL at pH < 2 and 0.03 mg/mL at pH >4; it was determined that a gastric transfer dissolution method that simulates the transition of the dosage form from the stomach to the intestines would be most appropriate. This dissolution method is designed to capture the precipitation event that occurs with the existing drug product as drug dissolved in the stomach transitions to the neutral pH environment of the intestinal tract where its solubility is substantially less. It is this precipita- tion event that limits tetrabenazine absorption from the intestinal tract and creates significant variability. It is the goal of the new MR formulations to provided consistent release across the Gl tract; i.e. , control tetrabenazine release in the stomach and provide consistent drug release across the intestinal tract. Hence, the gastric transfer dissolution method is useful for the assessment of a composition's potential performance in-vivo.

All dissolution tests were conducted in a Vankel VK-7000 (Varian, Inc.) USP apparatus I I (paddle) dissolution tester. The dissolution media was maintained at 37°C with a recirculating heater and a paddle speed of 50 RPM was used throughout the test. The equivalent of 100 mg of tetrabenazine was added to each vessel (4 x 25 mg tablets). The gastric phase of the test was conducted in 500 mL of 0.1 M HCI for a theoretical concentration of 0.2 mg tetrabenazine/mL (2.4% of equilibrium solubility). At the point of the gastric transfer pH change i.e. after 2 hours, 167 mL of 0.2 M sodium phosphate tribasic buffer (pH = 12) was added to the vessel to bring the pH up to 6.8. The theoretical neutral phase drug concentration was 0.15 mg/mL (500% of equilibrium solubility). The point of pH change was varied during development. In some cases the pH change was triggered by time (1 or 2 hours). In other cases the pH change, was triggered by the extent of acid phase release. After the dog PK data was obtained, it was determined that the best correlation was achieved with a pH change at 2 hours therefore this time point was selected for the dissolution test conducted for the final clinical candidate tablet formulations (Figure 7).

The concentration of tetrabenazine in solution during the dissolution test was continu- ously measured using a Pion Spectra in-situ fiber-optic UV-diss system (Pion, Inc.) with a 5 mm path length probe tip. The second derivative correction was utilized to filter turbidity resulting from tetrabenazine precipitation in the neutral phase. A concentration measurement was obtained approximately every 30 seconds during the dissolution test.

Results:

Gastric transfer dissolution of the tablet formulations 4-14 are illustrated by dissolution profiles in Figures 5-6. Gastric transfer dissolution of tetrabenazine IR formulation (Xenazine) is illustrated in Figure 5 as comparison. Gastric transfer dissolution of the final clinical candi- date tablet formulations 5, 8, 10 and 11 together with tetrabenazine IR formulation (Xenazine) are illustrated in Figure 7.

As indicated by the results, the majority of the new MR formulations provided controlled release of tetrabenazine in the gastric phase and improved solubility in the intestinal phase relative to Xenazine. The one exception is Formulation 9 which showed greater precipitation in the intestinal phase relative to Xenazine. Formulation 9 was dosed in the dog PK study as a negative control to evaluate the predictive power of the dissolution test. As predicted by the dissolution test, Formulation 9 was a poor performer in dogs. All other formulations showed improved PK performance relative to Xenazine as would be expected based on these dissolution results. Further, the rank order of C_max for the four clinical candidate formulations by in-vitro dissolution testing matches that of the C_max from the dog PK study. Therefore, it appears that the gastric transfer dissolution test developed for this program may be predictive of in-vivo performance. Example 7: Pharmacokinetic experiments in dogs

The purpose of this study was to provide comparative pharmacokinetic data for oral dose formulations containing tetrabenazine following oral tablet administration to male beagle dogs. Further, the purpose of the dog PK study was to identify, from the tested prototypes, candidates to be further evaluated in a human bioavailability study. The study was conducted at Charles River Laboratories (CRL) in Wilmington, MA. The dosing materials were provided to CRL under ambient conditions and stored at room temperature until use.

A total of 38 male beagle dogs (plus 4 spare animals) were selected from the Test Facility's colony of non-naive animals. Eighteen dogs were utilized for two dose sessions with a washout period of at least 7 days between doses. Before each use, the animals were as- signed to the study based on acceptable health as determined by a test facility veterinarian following a pre-study health status check. The pre-study health status check included a physical exam, serum chemistry and hematology evaluations. The animals were placed into fourteen groups of four animals per group. All animals were fasted overnight prior to dosing and food was returned after the 4 hour post-dose blood collection.

By the original study design, a 20 mL post-dose flush of purified water was administered by oral gavage to each dog to ensure tablet transit down the esophagus and to facilitate disintegration in the stomach. However, the PK results obtained from Group 1 (Xenazine tablet) by this design did not represent the typical PK profile from humans and C_miK values were substantially lower than those obtained from previous dog toxicokinetic studies. Therefore, it was hypothesized that insufficient post-dose fluid volume was administered to ensure tablet disintegration and tetrabenazine dissolution. Furthermore, it was recognized that given the pH solubility profile of tetrabenazine the post dose flush should be at a pH of less than 3 to facili- tate tetrabenazine dissolution in the stomach and better represent the condition in humans. Accordingly, the study design was amended to include a postdose flush of 40 mL of acidified water (pH = 2). When Xenazine was re-dosed with the acid flush, the PK profile was found to match that of humans, i.e. , elevated C_max levels followed by rapid elimination. Based on these results, the decision was made to dose all prototype tablets with the post-dose acid flush.

Each group of animals received the tetrabenazine formulation as a single oral tablet at a target dose level of 25 mg of tetrabenazine. Immediately after dosing, each animal received the oral flush indicated to assist in swallowing and dissolution of the tablet. Dosing was completed without incident. Following dosing and at each sample collection time point the animals were observed for any clinically relevant abnormalities and none were noted.

Bioanalytical method:

Whole blood samples (1 mL each; K2EDTA anticoagulant) were collected from each animal by direct venipuncture of a cephalic vein. Whole blood samples were collected from each animal at 0.5, 1 , 1.5, 2, 3, 4, 6, 8, 12 and 24 hours after oral dose administration. All whole blood samples were placed on ice immediately after collection and were centrifuged at 2-8°C to isolate plasma. The resulting plasma was transferred to individual polypropylene tubes and immediately placed on dry ice until storage at nominally -20°C before transfer to the test facility's bioanalysis group for concentration analysis.

The plasma samples were analyzed for concentrations of tetrabenazine and the metabolites trans-dihydrotetrabenazine and cis-dihydrotetrabenazine using a Research Grade LC-MS/MS Assay (RGA-Level 1 ) under Charles River study number 20042424. Following completion of the analysis, all residual plasma samples were stored at nominally -20°C.

Pharmacokinetic parameters were estimated from the plasma concentration-time data for the sum of tetrabenazine parent and the two metabolites using standard non- compartmental methods and utilizing suitable analysis software (Watson 7.2 Bioanalytical LI MS, Thermo Electron Corp). Pharmacokinetic parameters appropriate for the available plasma data and dose route (AUC_0-i_ast, AUC₀-i_nf, C_m£K, T_m;K, t_{1 2}) were reported. PK analysis was conducted based on total tetrabenazine plasma concentrations by summing the parent and the two metabolites as well as on the individual concentrations.

PK parameters for formulations 4-14 as well as for the tetrabenazine IR formulation (Xenazine) are listed in Table 5 below.

Table 5: Mean (CV%) PK parameters based on plasma concentrations of the sum of tetra- benazine parent and cis- and trans-dihydrotetrabenazine from oral administration to male beagle dogs (n=4).

Tablet formulation Tetrabena-

PK paramezine IR for4 5 6 7 8 ter

mulation

Co™ (ng/mL) 300 (78%) 190 (63%) 169 (36%) 177 (21%) 143(38%) 151 (37%) max (hr) 1.13(22%) 1.13 (22%) 1.25 (23%) 1.75(50%) 1.25 (23%) 1.75 (29%)

AUC₀.|_ast

846 (64%) 806 (34%) 913 (37%) 706 (24%) 605 (38%) 899 (58%) (hr ng/mL)

AUC₀,_nf

(observed) 860 (63%) 817 (38%) 947 (39%) 714 (24%) 613 (38%) 924 (59%)

(hr-ng/mL)

Lambda_z 0.166 (28%) 0.218(25%) 0.156 (29%) 0.198 (12%) 0.191 (5%) 0.167 (14%)

4.50 (36%) 3.36 (29%) 4.70 (23%) 3.54 (11%) 3.63 (5) 4.22 (14%) z (hr)

Cma/AUCo-inf

0.346 0.232 0.178 0.248 0.234 0.164

(hr^"1)

The ratio of C_max to AUCo._inr was proposed to best illustrate C_max blunting with respect to maintaining or improving total exposures. It is seen from Table 5 that Formulations 5, 8, 10 and 11 are the best performers with respect to this ratio. Therefore, it is believed that these formulations would be the preferred candidates for providing the desired human PK profile, i.e. , C_max reduced by 30 - 50% versus Xenazine with equivalent or improved total exposure (AUC).

It is furthermore seen from Table 5 that several of the new formulations show substantial reduction in variability of C_max compared to Xenazine, with Formulations 5, 6, 7, 8, 10, and 11 demonstrating the lowest variability. It is important to note that Formulation 9 was included in the study as a negative control based on poor in-vitro dissolution performance. It is therefore not surprising that this formulation exhibits the highest variability of those tested. The excessive PK variability of the current Xenazine IR product represents a substantial limitation of the therapy. Therefore, it is expected that the selected new MR formulations would provide improved tetrabenazine therapy by mitigating the erratic nature of the drug in an IR formula- tion.

The mean total tetrabenazine plasma concentration-versus-time profiles for each individual formulation relative to Xenazine are provided in Figures 8-18. It is seen from these figures that in most cases the new formulations provided reduced C_max concentrations and improved late-phase absorption of tetrabenazine relative to Xenazine.

Example 8: Pharmacokinetic experiments in humans

The purpose of this study was to provide comparative pharmacokinetic data for oral dose tablet formulations containing tetrabenazine following oral tablet administration to hu- mans, The further objective was to investigate the food effect of the final tablet formulations on the PK profile.

The study was conducted as a single center, single dose, open-label, nonrandomized, sequential, five-way crossover BA study in a single group of healthy subjects over a period of six to seven weeks. Each subject received the following treatments:

Period 1 : Treatment A: Tetrabenazine IR 25 mg tablet (Xenazine®) fasted (reference) Period 2: Treatment B: Tetrabenazine MR 25 mg final tablet formulation 10 fasted

Period 3: Treatment C: Tetrabenazine MR 25 mg final tablet formulation 11 fasted

Period 4: Treatment D: Tetrabenazine MR 25 mg final tablet formulation 8 fasted

Period 5: Treatment E: Tetrabenazine MR 25 mg final tablet formulation 5 fasted

Period 6: Treatment F: Tetrabenazine MR 25 mg final tablet formulation 11 after a high-fat meal (fed state).

After Period 5, Formulation 11 was selected for administration with a high-fat meal in Period 6. Subjects was admitted to the clinical unit on the evening prior to drug administration (Day-1 ) and confined to the clinical unit until 48 hours post the Period 5 (Day 15) dose. Subjects returned to the clinical unit for Period 6 and remained confined until 72 hours post the Period 6 dose.

Treatments A, B, C, D and E in Periods 1 to 5 were administered after an overnight fast (of at least eight hours). There was be a minimum washout of 72 hours between each administration for Period 1 to Period 5 and seven to ten days between Period 5 and Period 6 allowing sufficient time for the selection of the prototype for the food effect portion of the study. The study was conducted using one treatment group across a total of six study peri- ods. 12 healthy subjects were dosed to ensure available data for at least eight subjects.

The main criteria for inclusion that each subject had to meet to be enrolled in the study were as follows:

1. Male and female subjects aged 18 to 45 years (inclusive)

2. Body Mass Index (BM I) 18 to 30 kg/m2.

3. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) concentrations at screening and baseline that are less than or equal to the laboratory range upper limit of normal (ULN) for both analytes.

4. Corrected QT interval using Fridericia's formula (QTcF) that is <450 ms at screening.

The key criteria for exclusion of a subject from enrollment in the study were as follows: 1. Subjects with the following contraindications for Xenazine:

a. Subjects who are actively suicidal, or who have depression which is untreated or undertreated,

b. Subjects with impaired hepatic function,

c. Subjects taking monoamine oxidase inhibitors (MAOIs) or reserpine.

2. Poor metabolizers of cytochrome P450 2D6 (CYP2D6).

3. Subjects with a history of drug or alcohol abuse (in the past two years) or positive blood alcohol Breathalyzer test at Screening or the first clinic admission (Day -1 ). In addition, subjects with a positive urine drug screen test or positive blood alcohol Breathalyzer test at the time of the second clinic admission prior to study Period 6 was discontinued from the study.

PK assessment:

Blood samples were collected via an indwelling cannula or by venipuncture at the following times: Pre-dose (within 30 minutes of dosing) and at 0.25, 0.5, 1 , 1 .5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24 and 36 hours after dosing. Plasma concentrations of tetrabenazine, cis- dihydrotetrabenazine and trans-dihydrotetrabenazine were measured.

The concentration-time data was analyzed, using industry standard software using appropriate noncompartmental techniques to obtain estimates of the following derived PK pa- rameters: area under the curve calculated up to 24 hours (AUC₀.24), area under the curve calculated up to the last quantifiable plasma concentration (AUC_Wasl), area under the curve calculated up to the last plasma level time point (AUCo._inf), % AUC extrapolated, maximum plasma concentration (C_max), time of maximum plasma concentrations T_mtK, apparent elimination half-life (t½), elimination phase rate constant (lambda-z), absorption rate constant (ka) and mean residence time (MRT). C_max and T_miK were obtained directly from a visual inspection of the data while non-compartmental analysis was used to obtain the remaining parameters.

PK parameters for the final tablet formulations 5, 8, 10 and 11 well as for the tetrabenazine IR formulation (Xenazine) are listed in Tables 6-8 below.

In Tables 6 and 8, the PK parameters obtained from the human PK study are based on the sum of the plasmaconcentrations of tetrabenazine, cis-dihydrotetrabenazine and trans- dihydrotetrabenazine. In Table 7, the PK parameters are based only on plasma concentrations of trans-dihydrotetrabenazine. Table 6: Mean (%C V) PK parameters based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans-dihydrotetrabenazine from oral administration to fasted humans (n=12)

It is seen from Table 6 that for the sum of all three analytes both the C_ma)< and the ratio of C_max to AUCo-inf in fasted humans are reduced for all the final tablet formulations relative to Xenazine. All the final tablet formulations also show a minor reduction in variability of C_ma[ compared to Xenazine when tested in human, and in fasted humans all final tablet formulations furthermore have a prolonged T_max relative to Xenazine

The mean total tetrabenazine plasma concentration-versus-time profiles for each individual formulation relative to Xenazine are provided in Figure 19. It is seen from the Figure 19 that the new formulations provided reduced C_max concentrations and improved late-phase absorption of tetrabenazine relative to Xenazine.

In table 7, the PK parameters obtained from the human PK study are based on the plasmaconcentrations of trans-dihydrotetrabenazine as this is the active metabolite of tetrabenazine. Table 7 was included to illustrate PK of the pharmacologically active form of tetrabenazine. In Table 7, the plasma concentrations of tetrabenazine have not been taken into account since the C_ma!< did never exceed 1.1 ng/mL except for subject 12. Likewise, the plasma concentrations of cis-dihydrotetrabenazine have not been taken into account since this metabolite is inactive.

Table 7: Mean (%CV) PK parameters based on plasma concentrations of trans-

It appears from Table 7 that it also accounts for trans-dihydrotetrabenazine taken on its own that both the C_max and the ratio of C_max to AUC₀._inf in fasted humans are reduced for all the final tablet formulations relative to Xenazine. All the final tablet formulations also show a minor reduction in variability of C_max compared to Xenazine and all final tablet formulations furthermore have a prolonged T_max relative to Xenazine. It must be emphasized that the PK data based on plasma concentrations of solely trans-dihydrobenazine do not only reflect the properties of the MR formulations compared to xenazine but also reflect the degree of metabolilsm in the individual subjects. Formulation 11 was selected for further PK evaluation by administration with a high-fat meal. Table 8 below compares PK parameters in human obtained by giving tetrabenazinazine in fasted and fed state, respectively. The PK parameters of Table 8 are based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans-dihydrotetrabenazine from oral administration fed or fasted in humans (n=12)

Table 8: Mean (%CV) PK parameters of final tablet formulation 11 based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans-dihydrotetrabenazine from oral administration fed or fasted in humans (n=12)

When given with a high-fat meal there was an increase in the rate and extent of absorption of tetrabenazine compared to the same formulation given in fasted state. Increase in C_max was from 23.37 (fasting) to 36.97 (fed) ng/mL while increase in AUC₀-_inf was from 238.8 (fasting) to 319.6 (fed) hr- ng/mL.

Formulation 11 given in fed state produced C_ma)< lower than that attained with IR formulation given in fasted state [36.97 (formulation 11 , fed) vs. 51.56 (IR, fasted) ng/mL]. This finding indicates that formulation 11 given in fed state did not result in burst-type release in the stomach; otherwise C_max would have been similar with IR (fasted) and formulation 11 (fed) formulations. Instead there was increase in the rate and extent of tetrabenazine oral absorption (Table 6, column 2 vs. Table 8, column 3).

Claims

1. A solid dispersion comprising tetrabenazine in amorphous form.

The solid dispersion according to claim 1 , wherein the total amount of tetrabenazine constitutes 5-35% (w/w), such as 1 0-25% (w/w) of said solid dispersion.

The solid dispersion according to claim 2, wherein the total amount of tetrabenazine constitutes 18-22% such as 20% (w/w) of said solid dispersion.

The solid dispersion according to any of claims 1-3, comprising a polymer or a combination of at least two polymers.

The solid dispersion according to any of claims 1-4, comprising a polymer selected from Hypromellose E3, Hypromellose E5, Hypromellose E50 and Hypromellose E15 or a combination thereof.

The solid dispersion according to claim 5, wherein said Hypromellose E3, Hypromellose E5, Hypromellose E50, Hypromellose E15 or said combination thereof is further combined with Copovidone 64.

7. The solid dispersion according to any of claims 4-6, wherein said polymer or polymer combination constitutes 60-80% (w/w), such as 70-76% (w/w) of said solid dispersion. 8. The solid dispersion according to claim 7, wherein said polymer or polymer combination constitutes 72-74% (w/w) of said solid dispersion.

The solid dispersion according to any of claims 4-8, further comprising an antioxidant or a combination of at least two antioxidants.

The solid dispersion according to any of claim 9, wherein said antioxidant is sodium ascorbate.

The solid dispersion according to claim 9, wherein said at least two antioxidants are selected from sodium ascorbate, butylated hydroxyanisole and butylated hydroxytolu- ene.

INCORPORATED BY REFERENCE (RULE 20.6)

12. The solid dispersion according to any of claims 4-11 , further comprising a lubricant.

The solid dispersion according to claim 1 , wherein said lubricant is sodium stearyl fu ma rate.

The solid dispersion according to any of claims 1-13, wherein said solid dispersion corresponds to a solid dispersion selected from any of solid dispersion formulations 4- 8 or 10-14 in Table 1.

A pharmaceutical composition comprising tetrabenazine in amorphous form.

The pharmaceutical composition according to claim 15, wherein the total amount of tetrabenazine constitutes 5-35% (w/w), such as 5-25% (w/w) of said pharmaceutical composition.

The pharmaceutical composition according to claim 16, wherein the total amount of tetrabenazine constitutes about 10-20% (w/w) of said pharmaceutical composition.

A pharmaceutical composition comprising a solid dispersion according to any of claims 1-14.

The pharmaceutical composition according to claim 18, wherein said solid dispersion constitutes 60-98% (w/w) of said pharmaceutical composition.

The pharmaceutical composition according to any of claims 15-19 further comprising one or more pharmaceutically acceptable excipients.

The pharmaceutical composition according to claim 20, wherein said pharmaceutically acceptable excipients are selected from one or more of e.g. mannitol, colloidal silicon dioxide, croscarmellose sodium, carboxymethylcellulose sodium and sodium stearyl fu ma rate.

The pharmaceutical composition according to any of claims 15-21 , wherein said pharmaceutical composition corresponds to a composition selected from any of tablet formulations 4-8 or 10-14 of Table 3.

INCORPORATED BY REFERENCE (RULE 20.6)

23. The pharmaceutical composition according to any of claims 15-21 , wherein said pharmaceutical composition corresponds to a composition selected from any of tablet formulations 5, 8, 10 and 11 of Table 4.

The pharmaceutical composition according to any of claims 15-23, which provides a dissolution profile wherein not more than 90% such as not more than 80% of the total amount of tetrabenazine added to the vessel has been released from said composition at 2 hours, when said dissolution profile arises from a dissolution experiment performed with an equivalent of 100 mg of tetrabenazine added to a vessel containing 500 mL of 0.1 M HCI wherein 167 mL 0.2 M sodium phosphate tribasic buffer (pH 12) is added to the vessel at 2 hours, wherein said dissolution experiment is performed in a Vankel VK-7000 USP apparatus II (paddle) dissolution tester at 37°C at a paddle speed of 50 RPM.

The pharmaceutical composition according to any of claims 15-24, which provides a dissolution profile wherein 30-70% of the total amount of tetrabenazine added to the vessel is in solution at 4 hours, when said dissolution profile arises from a dissolution experiment performed with an equivalent of 100 mg of tetrabenazine added to a vessel containing 500 mL of 0.1 M HCI wherein 167 mL 0.2 M sodium phosphate tribasic buffer (pH 12) is added to the vessel at 2 hours, wherein said dissolution experiment is performed in a Vankel VK-7000 USP apparatus II (paddle) dissolution tester at 37°C at a paddle speed of 50 RPM.

The pharmaceutical composition according to claim 25, which provides a dissolution profile wherein 40-60% of the total amount of tetrabenazine added to the vessel is in solution at 4 hours.

The pharmaceutical composition according to any of claims 15-26, which provides a dissolution profile wherein 30-60% of the total amount of tetrabenazine added to the vessel is in solution at 6 hours, when said dissolution profile arises from a dissolution experiment performed with an equivalent of 100 mg of tetrabenazine added to a vessel containing 500 mL of 0.1 M HCI wherein 167 mL 0.2 M sodium phosphate tribasic buffer (pH 12) is added to the vessel at 2 hours, wherein said dissolution experiment is performed in a Vankel VK-7000 USP apparatus II (paddle) dissolution tester at 37°C at a paddle speed of 50 RPM.

INCORPORATED BY REFERENCE (RULE 20.6)

28. The pharmaceutical composition according to claim 27, wherein said pharmaceutical composition provides a dissolution profile wherein 40-50% of the total amount of tetrabenazine added to the vessel is in solution at 6 hours.

The pharmaceutical composition according to any of claims 15-28, which provides a PK profile in a beagle dog wherein C_mai is less than 250 ng/mL; when said PK profile arises from a PK experiment performed in a beagle dog fasted overnight prior to dosing with food returned at 4 hours, wherein said beagle dog immediately after dosing receives an oral flush of 40 mL acidified water (pH 2); wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans- dihydrotetrabenazine; and wherein said pharmaceutical composition comprises tetrabenazine in an amount of 25 mg.

The pharmaceutical composition according to claim 29, which provides a PK profile in a beagle dog wherein C_max is less than 225 ng/mL, such as less than 200, 175, 150 or 125 ng/mL.

The pharmaceutical composition according to any of claims 15-30, which provides a PK profile in a beagle dog wherein the C_max standard deviation is less than 60%; when said PK profile arises from a PK experiment performed in a beagle dog fasted overnight prior to dosing with food returned at 4 hours, wherein said beagle dog immediately after dosing receives an oral flush of 40 mL acidified water (pH 2); wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans-dihydrotetrabenazine.

The pharmaceutical composition according to claim 31 , which provides a PK profile in a beagle dog wherein the C_max standard deviation is less than 50%, such as less than 45, 40, 35, 30, 25 or 20.

The pharmaceutical composition according to any of claims 15-32, which provides a PK profile in a beagle dog wherein C_max is less than 65%, such as less than 60, 55, 50, 45, 40, 35 or 30% of the C_max obtained by an IR formulation comprising the same amount of tetrabenazine as said pharmaceutical composition; when said PK profile arises from a PK experiment performed in a beagle dog fasted overnight prior to dosing with food returned at 4 hours, wherein said beagle dog immediately after dosing receives an oral flush of 40 mL acidified water (pH 2); wherein said PK profile is based

INCORPORATED BY REFERENCE (RULE 20.6) on plasma concentrations of the sum of tetrabenazine parent and cis- and trans- dihydrotetrabenazine.

The pharmaceutical composition according to claim 33, which provides a PK profile in a beagle dog wherein C_max is in the range of 25-60%, such as in the range of 30-55 or 35-50% of the C_max obtained by an IR formulation comprising the same amount of tetrabenazine as said pharmaceutical composition.

35. The pharmaceutical composition according to any of claims 15-34, which provides a PK profile in a beagle dog wherein C_max/AUC_0-inf is in the range of 0.05-0.25 IT¹, such as in the range of 0.10-0.20 or 0.12-0.1 8 h^"1 ; when said PK profile arises from a PK experiment performed in a beagle dog fasted overnight prior to dosing with food returned at 4 hours, wherein said beagle dog immediately after dosing receives an oral flush of 40 ml_ acidified water (pH 2) ; wherein said PK profile is based on plasma con- centrations of the sum of tetrabenazine parent and cis- and trans- dihydrotetrabenazine.

The pharmaceutical composition according to any of claims 15-35, which provides a PK profile in a human wherein C_max is less than 50 ng/mL; when said PK profile arises from a PK experiment performed in a human fasted overnight for at least eight hours prior to dosing; wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans-dihydrotetrabenazine; and wherein said pharmaceutical composition comprises tetrabenazine in an amount of 25 mg.

The pharmaceutical composition according to claim 36, which provides a PK profile a human wherein C_max is less than 45 ng/mL, such as less than 40, 35, 30 or 25 ng/mL.

The pharmaceutical composition according to any of claims 15-37, which provides a PK profile in a human wherein the C_max standard deviation is less than 60%; when said PK profile arises from a PK experiment performed in a human fasted overnight for at least eight hours prior to dosing; wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans- dihydrotetrabenazine; and wherein said pharmaceutical composition comprises tetrabenazine in an amount of 25 mg.

INCORPORATED BY REFERENCE (RULE 20.6)

39. The pharmaceutical composition according to claim 38, which provides a PK profile in a human wherein the C_max standard deviation is less than 55%, such as less than 50, 45 or 40%. 40. The pharmaceutical composition according to any of claims 15-39, which provides a PK profile in a human wherein C_miK is less than 70% such as less than 65, 60, 55, 50, 45, 40 or 35 % of the C_max obtained by an IR formulation comprising the same amount of tetrabenazine as said pharmaceutical composition; when said PK profile arises from a PK experiment performed in a human fasted overnight for at least eight hours prior to dosing; wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans-dihydrotetrabenazine; and wherein said pharmaceutical composition comprises tetrabenazine in an amount of 25 mg.

41. The pharmaceutical composition according to claim 40, which provides a PK profile in a human wherein C_max is in the range of 35-70%, such as in the range of 40-70 or 40- 65% of the Cm_ax obtained by an IR formulation comprising the same amount of tetrabenazine as said pharmaceutical composition.

42. The pharmaceutical composition according to any of claims 15-41 , which provides a PK profile in a human wherein C_max/AUC₀-i_nf is in the range of 0.05-0.20 h^"1, such as in the range of 0.08-0.17 or 0.10-0.15 h^"1; when said PK profile arises from a PK experiment performed in a human fasted overnight for at least eight hours prior to dosing; wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans-dihydrotetrabenazine; and wherein said pharmaceutical composition comprises tetrabenazine in an amount of 25 mg.

43. A pharmaceutical composition comprising tetrabenazine, which provides a dissolution profile wherein not more than 90% such as not more than 80% of the total amount of tetrabenazine added to the vessel has been released from said composition at 2 hours, when said dissolution profile arises from a dissolution experiment performed with an equivalent of 100 mg of tetrabenazine added to a vessel containing 500 mL of 0.1 M HCI wherein 167 mL 0.2 M sodium phosphate tribasic buffer (pH 12) is added to the vessel at 2 hours, wherein said dissolution experiment is performed in a Vankel VK-7000 USP apparatus II (paddle) dissolution tester at 37°C at a paddle speed of 50 RPM.

INCORPORATED BY REFERENCE (RULE 20.6)

44. A pharmaceutical composition comprising tetrabenazine, which provides a dissolution profile wherein 30-70% of the total amount of tetrabenazine added to the vessel is in solution at 4 hours, when said dissolution profile arises from a dissolution experiment performed with an equivalent of 100 mg of tetrabenazine added to a vessel containing 500 ml_ of 0.1 M HCI wherein 167 mL 0.2 M sodium phosphate tribasic buffer (pH 12) is added to the vessel at 2 hours, wherein said dissolution experiment is performed in a Vankel VK-7000 USP apparatus II (paddle) dissolution tester at 37°C at a paddle speed of 50 RPM

The pharmaceutical composition according to claim 43, which provides a dissolution profile wherein 30-70% of the total amount of tetrabenazine added to the vessel is in solution at 4 hours.

The pharmaceutical composition according to any of claims 44-45, which provides a dissolution profile wherein 40-60% of the total amount of tetrabenazine added to the vessel is in solution at 4 hours.

A pharmaceutical composition comprising tetrabenazine, which provides a dissolution profile wherein 30-60% of the total amount of tetrabenazine added to the vessel is in solution at 6 hours, when said dissolution profile arises from a dissolution experiment performed with an equivalent of 100 mg of tetrabenazine added to a vessel containing 500 mL of 0.1 M HCI wherein 167 mL 0.2 M sodium phosphate tribasic buffer (pH 12) is added to the vessel at 2 hours, wherein said dissolution experiment is performed in a Vankel VK-7000 USP apparatus II (paddle) dissolution tester at 37°C at a paddle speed of 50 RPM

The pharmaceutical composition according to any of claims 43-46, which provides a dissolution profile wherein 30-60% of the total amount of tetrabenazine added to the vessel is in solution at 6 hours.

The pharmaceutical composition according to any of claims 47-48, which provides a dissolution profile wherein 40-50% of the total amount of tetrabenazine added to the vessel is in solution at 6 hours.

A pharmaceutical composition comprising tetrabenazine, which provides a PK profile in a beagle dog wherein C_max is less than 250 ng/mL; when said PK profile arises from a PK experiment performed in a beagle dog fasted overnight prior to dosing with food

INCORPORATED BY REFERENCE (RULE 20.6) returned at 4 hours, wherein said beagle dog immediately after dosing receives an oral flush of 40 mL acidified water (pH 2); wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans- dihydrotetrabenazine; and when said pharmaceutical composition comprises tetra- benazine in an amount of 25 mg.

The pharmaceutical composition according to any of claims 43-49, which provides a PK profile in a beagle dog wherein C_max is less than 250 ng/mL; when said PK profile arises from a PK experiment performed in a beagle dog fasted overnight prior to dosing with food returned at 4 hours, wherein said beagle dog immediately after dosing receives an oral flush of 40 mL acidified water (pH 2); wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans- dihydrotetrabenazine; and when said pharmaceutical composition comprises tetrabenazine in an amount of 25 mg.

The pharmaceutical composition according to any of claims 50-51 , which provides a PK profile in a beagle dog wherein C_max is less than 225 ng/mL, such as less than 200, 175, 150 or 125 ng/mL.

A pharmaceutical composition comprising tetrabenazine, which provides a PK profile in a beagle dog wherein the Cmax standard deviation is less than 60%; when said PK profile arises from a PK experiment performed in a beagle dog fasted overnight prior to dosing with food returned at 4 hours, wherein said beagle dog immediately after dosing receives an oral flush of 40 mL acidified water (pH 2) ; v/herein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans-dihydrotetrabenazine.

The pharmaceutical composition according to any of claims 43-52, which provides a PK profile in a beagle dog wherein the C_max standard deviation is less than 60%; when said PK profile arises from a PK experiment performed in a beagle dog fasted overnight prior to dosing with food returned at 4 hours, wherein said beagle dog immediately after dosing receives an oral flush of 40 mL acidified water (pH 2) ; wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans-dihydrotetrabenazine.

INCORPORATED BY REFERENCE (RULE 20.6) The pharmaceutical composition according to any of claims 53-54, which provides a PK profile in a beagle dog wherein the C_max standard deviation is less than 50%, such as less than 45, 40, 35, 30, 25 or 20%. 56. A pharmaceutical composition comprising tetrabenazine, which provides a PK profile in a beagle dog wherein C_ma[ is less than 65%, such as less than 60, 55, 50, 45, 40, 35 or 30% of the C_ma>; obtained by an IR formulation comprising the same amount of tetrabenazine as said pharmaceutical composition; when said PK profile arises from a PK experiment performed in a beagle dog fasted overnight prior to dosing with food returned at 4 hours, wherein said beagle dog immediately after dosing receives an oral flush of 40 mL acidified water (pH 2); wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans- dihydrotetrabenazine. 57. The pharmaceutical composition according to any of claims 43-55, which provides a PK profile in a beagle dog wherein C_max is less than 65%, such as less than 60, 55, 50, 45, 40, 35 or 30% of the C_max obtained by an IR formulation comprising the same amount of tetrabenazine as said pharmaceutical composition; when said PK profile arises from a PK experiment performed in a beagle dog fasted overnight prior to dosing with food returned at 4 hours, wherein said beagle dog immediately after dosing receives an oral flush of 40 mL acidified water (pH 2); wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans- dihydrotetrabenazine.

The pharmaceutical composition according to any of claims 56-57, which provides a PK profile in a beagle dog wherein C_max is in the range of 25-60%, such as in the range of 30-55 or 35-50% of the C_ma>< obtained by an IR formulation comprising the same amount of tetrabenazine as said pharmaceutical composition.

A pharmaceutical composition comprising tetrabenazine, wherein said pharmaceutical composition provides a PK profile in a beagle dog wherein C_max/AUC₀.i_nf is in the range of 0.05-0.25 h^"1, such as in the range of 0. 0-0.20 or 0.12-0.1 8 h^"1 ; when said PK profile arises from a PK experiment performed in a beagle dog fasted overnight prior to dosing with food returned at 4 hours, wherein said beagle dog immediately after dosing receives an oral flush of 40 mL acidified water (pH 2); wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans-dihydrotetrabenazine.

INCORPORATED BY REFERENCE (RULE 20.6)

60. The pharmaceutical composition according to any of claims 43-58, which provides a PK profile in a beagle dog wherein C_max/AUCo-in_f is in the range of 0.05-0.25 h^"1, such as in the range of 0.10-0.20 or 0.12-0.18 h^"1; when said PK profile arises from a PK experiment performed in a beagle dog fasted overnight prior to dosing with food returned at 4 hours, wherein said beagle dog immediately after dosing receives an oral flush of 40 ml. acidified water (pH 2); wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans- dihydrotetrabenazine.

61 . A pharmaceutical composition comprising tetrabenazine, which provides a PK profile in a human wherein C_ma; is less than 50 ng/mL; when said PK profile arises from a PK experiment performed in a human fasted overnight for at least eight hours prior to dosing; wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans-dihydrotetrabenazine; and wherein said pharmaceutical composition comprises tetrabenazine in an amount of 25 mg.

62. The pharmaceutical composition according to any of claims 43-60, which provides a PK profile in a human wherein C_max is less than 50 ng/mL; when said PK profile arises from a PK experiment performed in a human fasted overnight for at least eight hours prior to dosing; wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans-dihydrotetrabenazine; and wherein said pharmaceutical composition comprises tetrabenazine in an amount of 25 mg.

63. The pharmaceutical composition according to any of claims 61-62, which provides a PK profile in a human wherein C_max is less than 45 ng/mL, such as less than 40, 35, 30 or 25 ng/mL.

64. A pharmaceutical composition comprising tetrabenazine, which provides a PK profile in a human wherein the C_mai standard deviation is less than 60%; when said PK profile arises from a PK experiment performed in a human fasted overnight for at least eight hours prior to dosing; wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans-dihydrotetrabenazine: and wherein said pharmaceutical composition comprises tetrabenazine in an amount of 25 mg.

INCORPORATED BY REFERENCE (RULE 20.6)

65. The pharmaceutical composition according to any of claims 43-63, which provides a PK profile in a human wherein the C_max standard deviation is less than 60%; when said PK profile arises from a PK experiment performed in a human fasted overnight for at least eight hours prior to dosing; wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans- dihydrotetrabenazine; and wherein said pharmaceutical composition comprises tetrabenazine in an amount of 25 mg.

66. The pharmaceutical composition according to any of claims 64-65, which provides a PK profile in a human wherein the C_max standard deviation is less than 55%, such as less than 50, 45 or 40%.

67. A pharmaceutical composition comprising tetrabenazine, which provides a PK profile in a human wherein C_max is less than 70%, such as less than 65, 60, 55, 50. 45, 40 or 35% of the C_ma>< obtained by an IR formulation comprising the same amount of tetrabenazine as said pharmaceutical composition; when said PK profile arises from a PK experiment performed in a human fasted overnight for at least eight hours prior to dosing; wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans-dihydrotetrabenazine; and wherein said pharma- ceutical composition comprises tetrabenazine in an amount of 25 mg.

68. The pharmaceutical composition according to any of claims 43-66, wherein said

pharmaceutical composition provides a PK profile in a human wherein C_ma)< is less than 70%, such as less than 65, 60, 55, 50, 45, 40 or 35% of the C_max obtained by an IR formulation comprising the same amount of tetrabenazine as said pharmaceutical composition; when said PK profile arises from a PK experiment performed in a human fasted overnight for at least eight hours prior to dosing; wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans-dihydrotetrabenazine; and wherein said pharmaceutical composition comprises tetrabenazine in an amount of 25 mg.

69. The pharmaceutical composition according to any of claims 67-68, which provides a PK profile in a human wherein C_miK is in the range of 35-70%, such as in the range of 40-70 or 40-65% of the C_max obtained by an IR formulation comprising the same amount of tetrabenazine as said pharmaceutical composition.

INCORPORATED BY REFERENCE (RULE 20.6)

70. A pharmaceutical composition comprising tetrabenazine, which provides a PK profile in a human wherein C_max/AUC₀-i_nf is in the range of 0.05-0.20 h^"1, such as in the range of 0.08-0.17 or 0.10-0.15 h^"1 ; when said PK profile arises from a PK experiment performed in a human fasted overnight for at least eight hours prior to dosing; wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans-dihydrotetrabenazine; and wherein said pharmaceutical composition comprises tetrabenazine in an amount of 25 mg.

71 . The pharmaceutical composition according to any of claims 43-69, which provides a PK profile in a human wherein C_max/AUC_0-in_f is in the range 0.05-0.20 h^"1, such as in the range of 0.08-0.17 or 0.10-0.15 h^"1; when said PK profile arises from a PK experiment performed in a human fasted overnight for at least eight hours prior to dosing; wherein said PK profile is based on plasma concentrations of the sum of tetrabenazine parent and cis- and trans-dihydrotetrabenazine; and wherein said pharmaceutical composition comprises tetrabenazine in an amount of 25 mg.

72. The pharmaceutical composition according to any of claims 50-60, wherein said PK profile arises from a PK experiment performed as described in Example 7. 73. The pharmaceutical composition according to any of claims 61-71 , wherein said PK profile arises from a PK experiment performed as described in Example 8.

74. The pharmaceutical composition according to any of claims 43-73, wherein said tet- rabazine in said pharmaceutical composition is tetrabenazine in amorphous form.

75. The pharmaceutical composition according to any of claims 15-74, wherein the total amount of tetrabenazine is in the range of 10-100 mg, such as 10, 15, 20, 25, 30, 35, 40, 50, 75 or 100 mg 76. The pharmaceutical composition according to claim 75, wherein the total amount of tetrabenazine is 25 mg.

77. The pharmaceutical composition according to any of claims 15-76, wherein said

pharmaceutical composition is an oral unit dosage form such as a tablet or a capsule.

78. The pharmaceutical composition according to claim 77, wherein said composition is a tablet.

INCORPORATED BY REFERENCE (RULE 20.6)

79. The pharmaceutical composition according to any of claims 15-78, wherein said tetra- benazine is the sole therapeutic agent comprised in said composition.

80. The pharmaceutical composition according to any of claims 15-79, further comprising a second therapeutic agent.

81. The pharmaceutical composition according to any of claims 15-80 for use in the

treatment of a hyperkinetic movement disorder such as Huntington's disease, hemi- ballismus, senile chorea, tic, tardive dyskinesia, myoclonus, dystonia and Tourette's syndrome.

82. A method for the treatment of a hyperkinetic movement disorder such as Huntington's disease, hemiballismus, senile chorea, tic, tardive dyskinesia, myoclonus, dystonia and Tourette's syndrome, by administration of a pharmaceutical composition according to any of claims 15-81 to a patient in need thereof.

INCORPORATED BY REFERENCE (RULE 20.6)